Abstract
Adipose tissue contains several types of stem and progenitor cells, including the adipose tissue-derived stromal cells (ADSCs), the endothelial progenitor cells, and the hematopoietic and immune system cells. ADSCs share most of phenotypical and functional characteristics of the mesenchymal stromal cell (MSC): the bone marrow-derived mesenchymal stromal cell (BM-MSC) or MSC presents in the cord blood, placenta, and umbilical cord. The basic function of ADSC is the preservation of the adipose tissue integrity by the production of adipocytes in the intensity proportional to their degradation. Recently it has been proven that the adipose tissue may contain more MSC-like cells than the bone marrow (which serve as the “gold standard” of cells available for autologous cellular therapies. ADSCs are not only able to differentiate into adipo-, chondro-, or osteogenic lineages but also participate in the formation of the endothelium; smooth, skeletal, or cardiac muscle; hepatocytes; or neural cells. It remains unclear in which extent adipose tissue serves as the natural depository of stem cells, supplying “on-demand” cells for tissue regeneration. ADSCs are the abundant source of autologous stem cells for regenerative medicine techniques, being present in humans throughout all their lifetime.
Access provided by Autonomous University of Puebla. Download chapter PDF
Similar content being viewed by others
Keywords
- Adipose Tissue
- Mesenchymal Stromal Cell
- Stromal Vascular Fraction
- Osteogenic Lineage
- Stromal Vascular Fraction Cell
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
Introduction
Adipose tissue contains several types of stem and progenitor cells, including the adipose tissue-derived stromal cells (ADSCs), the endothelial progenitor cells, and the hematopoietic and immune system cells. ADSCs share most of phenotypical and functional characteristics of the mesenchymal stromal cell (MSC): the bone marrow-derived mesenchymal stromal cell (BM-MSC) or MSC present in the cord blood, placenta, and umbilical cord. The basic function of ADSC is the preservation of the adipose tissue integrity by the production of adipocytes in the intensity proportional to their degradation. Recently it has been proven that the adipose tissue may contain more MSC-like cells than the bone marrow (which serves as the “gold standard” of cells available for autologous cellular therapies. ADSCs are not only able to differentiate into adipo-, chondro-, or osteogenic lineages but also participate in the formation of the endothelium; smooth, skeletal, or cardiac muscle; hepatocytes; or neural cells. It remains unclear in which extent adipose tissue serves as the natural depository of stem cells, supplying “on-demand” cells for tissue regeneration. ADSCs are the abundant source of autologous stem cells for regenerative medicine techniques, being present in humans throughout all their lifetime.
Adipose Tissue as a Source of Stem Cells
Adipose tissue derives from the mesodermal layer of the embryo [104, 122]. There are several types of adipose tissue, differing in localization and functions: white, mechanical, brown, mammary, and bone marrow. White adipose tissue provides mechanical insulation and energy supply and functions as an endocrine organ, producing the adipokine factors, such as leptin, adiponectin, resistin, osteopontin, lipocalin, and angiogenic-related factors. Mechanical adipose tissue is responsible for more specialized structural support, like palmary fat pads or retro-orbital supporting tissue. Brown adipose tissue plays a unique thermogenic function – being able to generate heat through expression of unique protein – it is localized around the aorta, heart, or kidney in newborn infants, and its volume decreases along with human maturation. Mammary adipose tissue is function specialized, providing the mechanical support and energy for the mammary glands during lactation. The role of the adipose tissue in bone marrow cavities is to replace in adults the space occupied in children by the bone marrow and to provide humoral support (cytokines) and contact regulatory signals for hematopoietic stem and progenitor cells.
Initially, the studies of cells isolated from the adipose tissue were concentrated on adipocytes and their precursors. As early as in 1966, Rodbell and Jones [137–139] were able to isolate the “stromal vascular fraction” (SVF) which was a heterogenous cell population with the predominance of adipocyte progenitors plus the admixture of the fibroblasts, pericytes, and endothelial and blood cells. Consecutive studies [41, 56] revealed that SVF cells have fibroblast-like morphology and are mitotically active source of adipocyte precursors capable to form adipose tissue in vitro. Some authors suggested [45] that under specific conditions, SVF is able to differentiate into non-adipogenic lineages. Almost a decade later, Zhuk et al. [188] demonstrated that the adipose tissue is a source of mesenchymal stromal-type cells (MSCs), capable to differentiate into adipo-, chondro-, myo-, and osteogenic lineages. Subsequently, the same authors demonstrated that the adipose tissue-derived ADSCs express the same marker composition (CD29+ CD44+, CD71+, CD90+, CD105+, SH3+, CD31−, CD34−, CD45−) as the bone marrow-derived mesenchymal stromal cell (BM-MSC) population [187]. The other less numerous population of adipose-derived cells is CD31+, CD34+, CD105+, and CD45− and consists of endothelial stem cells (ESCs), characterized by the low expansion rate in vitro [9].
ADSCs are integral component of the adipose tissue, being responsible for continuous replacement of aging adipocytes, resulting in remodeling, and continuous presence of the adipose tissue throughout all lifetime of human being. Several other stem cell populations may derive from the blood vessels (hematopoietic stem cells, immune system cells, or endothelial stem cells) or reside in “stem cell niches” in the adipose tissue following migration from other tissue locations.
Collection and Processing of ADSC
Elective suction-assisted lipectomy (liposuction) has been introduced as a technique of the elimination of the excessive amount of adipose during esthetic medicine treatment (body modification, weight reduction). Liposuction, being one of the basic tools of cosmetic surgery, offers the unique opportunity for collection of large quantities of stem cells from the waste material, without any ethical, medical, or religious contraindications. The same technique may be applied specifically for collection of autologous ADSC for regenerative medicine purposes. Liposuction is not only the less invasive technique as bone marrow aspiration; it allows to collect much higher numbers of cells of MSC characteristics when compared to bone marrow aspiration [24].
The adipose tissue may be obtained by tumescent lipoaspiration [81], ultrasound-assisted lipoaspiration [125], laser-assisted or water-assisted liposuction [2], or surgical resection – all these methods are considered as useful for stem cell collection (in our experience the highest percentage of viable cells is obtained by surgical resection, and the highest, although acceptable, cell mortality results from laser-assisted or ultrasound-assisted procedures). The best results are obtained when the storage time from adipose tissue collection till processing does not exceed 24 h [10].
All the existing protocols for adipose tissue-derived cell separation [8, 54, 123, 188] are based on the enzymatic digestion (collagenase, trypsin) and density gradient separation of ADSCs. Surgical isolation and mechanical dissection of fat, applied in pioneer works [74, 98], was replaced by various liposuction techniques, but all the rest of processing techniques remained basically unchanged. Following lipoaspiration, the mixture of the adipose tissue and balanced salt solution is washed with PBS (purification and removal of anesthetics and epinephrine used during tumescent liposuction) and digested with collagenase. Depending on the technique protocol, cells are isolated by centrifugation, erythrocytes removed by density gradient separation or by addition of erythrocyte lysis buffer, and resulting population of ADSC is expanded in plastic-adherent cultures in media without addition of any growth factors. Cytokine deprivation in in vitro culture allows for further purification of cell population by elimination of residual hematopoietic stem cells originating from blood vessels.
The increasing demand for ADSCs for cell-based therapies resulted in construction of automated systems for adipose-derived cell separation, which can be used at the bedside, without the access to of stem cell laboratory [21, 112]. The advantage of automated devices is (more or less) closed processing system and the possibility of applying cell-based therapies by the groups having no experience in stem cell processing. The disadvantage of automated ADSC processing “on the bedside” is temptation to neglect the verification step of obtained cellular material (tests of cell numbers, viability, phenotype characteristics, etc.) in situations, when cells are isolated by the machine and directly transplanted into patients by surgeons. The other disadvantage of automated system is the cost of the cell isolation procedure and lower flexibility of the procedure when dealing with the material of nontypical quantity or quality.
Phenotypical and Functional Characteristics of ADSC
The procedure of isolation of the adipose tissue-derived cells does not allow to purify the homogenous cell population, resulting in the separation of mixture of mesenchymal stromal cells (MSCs), adipocyte progenitors, fibroblasts, pericytes, and endothelial and blood cells. Such heterogenous population is described by the term “stromal vascular fraction” (SVF) [41, 56, 137–139] or “processed lipoaspirate” (PLA) [118, 188]. The population of adipose tissue-derived stromal cells (ADSCs) is purified by culture in plastic-adherent manner in media non-supplemented with growth factors. Cells which need the supplementation of culture media with growth factors (hematopoietic stem cells) will commit apoptosis, and the more differentiated cells will achieve mature stage and, being nonproliferating, will be eliminated during consecutive passages. The final cell population is composed predominantly of MSC type of cells and is described by various authors as adipose-derived adult cells (ADACs), adipose-derived stem cells (ADSCs, nomenclature advocated by International Fat Applied Technology Society), or adipose mesenchymal stem cells (AdMSCs). Since the “stemness” of adipose-derived cells is not formally proven, the acronym of “adipose-derived stromal cells” (ADSCs) seems most appropriate, reflecting both the adipose tissue origin and mesenchymal stromal characteristics of the cells.
There are several papers discussing the availability of ADSC in comparison with the bone marrow MSC (BM-MSC). The frequency of non-hematopoietic stem cells in human bone marrow, measured by CFU-F assay, varies between 1 in 25,000 and 1 in 100,000 [6, 7, 21, 118]. In contrast, ADSCs are present in frequency of 1 in 50 in population of adipose tissue-isolated nucleated cells [157]. The direct comparison of CFU-F numbers formed by ADSC or BM-MSC plated in the same frequencies of initial cells, revealed the sevenfold higher frequency of ADSC-derived CFU-F in comparison to BM-MSC-derived CFU-F [77]. Based on the frequency of MSC in the bone marrow, and frequency of adipose-derived cells, and on the approximate volume of the adipose tissue or bone marrow collected, it may be concluded that the adipose tissue is a more efficient source for cell collection for therapeutic purposes than the bone marrow [157].
Cell Surface Markers
Phenotypically, ADSCs express surface markers characteristic for MSC category, and, apart from minor differences, their phenotype is similar to BM-MSCs. Both ADSCs and BM-MSCs express markers common for cells having multilineage potential: STRO-1, CD105, and CD166 [26, 47, 48, 103, 128, 155]. The other markers suggesting the therapeutic potential of ADSC are CD29 (beta-1 integrin), important for inducing angiogenesis [4], intercellular adhesion molecule-1 ICAM-1 (CD54) immunoglobulin supergene family [141], and CD44 (hyaluronate receptor involved in development of extracellular matrix) [187]. ADSCs are HLA-DR negative, mostly MHC Class I positive [5], being of low immune reactivity when transplanted in HLA mismatch situation.
ADSCs fulfill the criteria for being multipotential stromal cells, proposed by the International Society for Cellular Therapy (in vitro plastic adherence; expression of CD105, CD73, and CD90 and lack of expression of CD45, CD34, and CD14 or CD11b, CD79a, or CD19 and HLA-DR surface molecules; and capacity of differentiation to osteoblasts, adipocytes, and chondroblasts [30, 57]).
The extended characterization of ADSC surface markers [5, 23, 24, 47, 110, 108, 187] revealed the presence of CD9, CD10, CD13, CD29, CD34, CD44, CD49d, CD49e, CD54, CD55, CD59, CD73, CD90, CD105, CD117, CD146, CD166, and STRO-1 markers and the absence of lineage-specific, hematopoietic, and endothelial markers CD3, CD4, CD11c, CD14, CD15, CD16, CD19, CD31, CD33, CD38, CD45, CD56, CD62p, CD104, and CD144. The expression of VLA-4 (CD49d) and its receptor VCAM-1 (CD106) is reciprocally reversed when comparing ADSC to BM-MSC: ADSCs express CD49d+/CD106- pattern [157], whereas BM-MSCs are CD49d-/CD106+ [23]. The concentration of CD34 marker was higher in freshly isolated cells (SVF) and remained present at reduced levels throughout the culture period of ADSC [110] or have been already unobserved by the others in at least 95 % of cultured cells [77]. Low percentage of CD34-positive cells may reflect the presence of subpopulation of endothelial progenitor cells (EPCs) – the possibility supported by the finding that adipose-derived CD34+ and CD133+ cells are able to form endothelial colonies in vitro or induce angiogenesis in vivo [11, 109, 130, 134, 160]. The concentration of EPC positively correlates with body index, suggesting the entrapment of these cells in the adipose tissue resulting in reduced angiogenic potential in obesity [168].
It has been also documented [15] that ADSCs express Toll-like receptors (TLR-1, TLR-2, TLR-3, TLR-4, TLR-5, TLR-6, and TLR-9) identified both by flow cytometry and real-time PCR. TLRs affect ADSC proliferation and differentiation and play a nonimmune role in signaling on ADSC, but their exact role as structures present on ADSC remains mostly unclear.
Proteome and Transcriptome Analysis
Mass spectrometry analyses revealed the similarities of ASC proteomes and proteomes of fibroblasts and MSCs [25, 161, 172]. Transcriptomes of ADSC and BM-MSC were studied by gene microarrays [75, 99, 175] or Affymetrix gene chips [40]. Both methods have revealed that ADSC and BM-MSC share a common transcriptome [40, 175], expressing stem cell-associated gene markers (Oct4, Sox2, and Rex1) [62].
In Vitro Proliferation and Differentiation of ADSC
ADSCs grow in vitro without supplementation with any growth factors. Fibroblastoid-like cells adhere to plastics and are passaged following trypsinization through a culture period up to 20 passages, or >4 months without visible loss of telomere length [37, 62]. The stable, low senescence level of ADSCs in culture was confirmed by the observation of the absence (<5 %) of β-galactosidase-positive cells in cultures from passage 1 to passage 15 [188]. Data on the telomerase activity are not consistent [40, 62, 75] and may depend on the observation protocols. Cell doubling time varies from 2 to 4 days [62, 110] being longest at the beginning of the culture. In both in vitro and in in vivo animal models, ADSCs are able to differentiate into several “mesenchymal” and “non-mesenchymal” lineages. Since only the minority of experiments were based on the analysis of single cell-derived clonal population of cells [187], the evidence of multilineage differentiation may be assigned rather to the “ADSC cell population” than to the single cell. It has been, nevertheless, proven that ADSC is able to differentiate into other mesenchymal cell lineages – the phenomenon interpreted by some authors as transdifferentiation or plasticity [130, 133, 145, 146].
Differentiation potential of cells residing in the adipose tissue resembles this of the MSC or MSC-like cells residing in the bone marrow (BM-MSC), umbilical cord Wharton jelly (umbilical cord stromal cells, UCSC), cord blood (unrestricted somatic stem cells, USSC), or placenta (reviewed in [131]). It is not surprising that cells resident in the adipose tissue are capable of adipogenic differentiation [28, 51, 144, 151, 187, 188] and, similarly to the other “MSC-type” cells, may differentiate into osteogenic [31, 50, 52, 53, 58, 70, 82, 83, 88, 124, 153, 164, 187, 188] or chondrogenic [32, 35, 128, 174, 175, 187, 188] lineages. The other directions of their differentiation in vitro are myogenic (skeletal muscle [90, 112, 187, 188], smooth muscle [1, 42, 65, 91], and cardiac muscle [44, 129, 156, 158, 179, 187, 188]), neurogenic [4, 71, 86, 142, 145–147, 187], pancreatic [165], and hepatic [152, 162, 163] lineages. It seems to be unclear, if observed angiogenic potential of adipose tissue-derived cells [3, 115, 130, 167] should be attributed to ADSC, EPC, or both cell types, since both are present in adipose tissue and both are capable of endothelial differentiation [130]. It has to be stressed, however, that the majority of experiments describing the differentiation potential of ADSC did not result in the observation of the formation of functional mature cells or tissues but allowed to deduce the differentiation capability from the identification of some structural markers or genetic profiles specific for the cell lineages – so the suggested “differentiation potential” does not mean that ADSCs are able to produce fully functional cells of specific lineage.
Interaction with Hematopoietic and Immune System
The earliest recognized function of mesenchymal stromal cells was formation of “niches” in the bone marrow, where MSC functioned as bone marrow microenvironment, supporting homing and proliferation of hematopoietic stem cells. It has been reported that co-infusion of BM-MSC and hematopoietic stem cells enhanced hematopoietic recovery in chemotherapy-treated patients [84]. ADSCs, being the MSC-type cells, are able to support hematopoiesis in lethally irradiated mice [18]. In intraperitoneal infusion of large quantities (107), ADSCs resulted in survival of 40 % of lethally irradiated mice [19], whose hematopoietic cells were of endogenous origin. In all reported experiments, ADSC did not differentiate per se into hematopoietic cells but, similarly to the physiological role of bone marrow MSCs, supported hematopoiesis, playing the role of hematopoietic microenvironment cells.
Mesenchymal stromal cells play an immunomodulatory role when infused into patients with graft-versus-host disease (GVHD) following bone marrow transplantation. It has been observed [87] that in vitro-expanded bone marrow MSCs are able to reduce GVHD symptoms and are efficient in treatment of steroid-resistant GVHD in bone marrow transplanted cancer patients. Comparison of BM-MSC and ADSC revealed similarity in the immunomodulatory properties of both cell types – ADSC did not provoke in vitro alloreactivity of incompatible lymphocytes, suppressed mixed lymphocyte reaction, and suppressed lymphocyte proliferative reaction to mitogens [132]. These findings opened the perspectives for ADSC clinical applications for treatment of patients with severe therapy-resistant GVHD [38, 180].
ADSC and Oncogenesis
There exists evidence on oncogenic potential of bone marrow-derived MSC. MSC may be involved in cancer induction or expansion in several ways – as normal cells supporting cancer growth by migrating towards tumors, modifying tumor environment (vasculogenesis), and immunosuppression or as cells undergoing spontaneous malignant transformation (reviewed in [114]). ADSCs, being a subpopulation belonging to the MSC family, do not differ significantly from BM-MSC in the probability of promotion or induction of carcinogenesis, although the experimental evidence, concerning ADSC role in oncogenesis, is much more scarce than their bone marrow-derived counterparts. Extensive study on the interrelation between ADSC and breast cancer cells [117] revealed that ADSCs are able to home to tumor site even when injected intravenously and incorporate into tumor vessels, where they differentiate into endothelial cells. Direct contact of ADSCs with tumor cells results in enhancement of secretion from ADSCs of stromal cell-derived factor 1 (SCF-1), which acts in a paracrine fashion on the cancer cells enhancing their motility, invasion, and metastases. It has been also documented that ADSCs, similarly to their interactions with breast cancer, were recruited towards cancer cells through SDF1/CXCR4 axis and supported cancer growth by increasing tumor vascularity when cocultured with prostate cancer cells in athymic mice [97].
Standard ex vivo expansion procedure, when ADSCs are cultured for 6–8 weeks, is “safe” and does not lead to the phase of cell transformation events. It has been documented, however, [143], that after in vitro expansion lasting 4–5 months, human or mouse ADSC spontaneously bypassed the senescence and crisis phase, showing altered phenotype and chromosome instability and losing contact inhibition capacity. At this stage, cells were able to induce cancer when injected into immunodeficient mice. The general conclusion from the observations on long-term expansion of ADSC is that the cells, expanded “traditionally” for the period of 6–8 weeks, may be considered as a valuable tool for tissue regeneration and engineering, but the prolonged in vitro culture may cause the risk of spontaneous transformation and induction of cancerogenesis in transplant host [143]. Contrary to the observations of the immortalization of ADSC, after prolonged in vitro culture, the aberrant, tumorigenic cell line was isolated as early as from third-passage cells [121] – the result suggesting the need of rigorous testing of in vitro-expanded ADSCs prior to their clinical applications.
Clinical Applications of ADSC
Subcutaneous Tissue Formation
The adipose tissue is present physiologically in multiple locations in human body, being responsible for multiple functions (mechanical, endocrine, thermoinsulatory, and energy supplying). Typical surgical procedures (liposuction, lipotransfer) are performed for cosmetic rather than medical purposes – the exemption is the application of lipotransfer technique for treatment of breast cancer patients after mastectomy, where injection of the adipose tissue not only partially reconstructs the amputated breast but locally supports better healing and prevents formation of connective tissue scar between the skin and muscles. Enrichment of lipotransferred autologous adipose tissue with ADSC isolated from the same patient [105, 184] reduces the atrophy of implanted tissue and supports the formation of new adipocytes in the region of implantation. Immunosuppressive potential of implanted ADSC may also minimize the inflammatory reaction in the implantation area. There is some consideration [101] if the implantation of ADSCs may increase the risk of cancer recurrence; however, such speculations seem to be not substantiated by the observations. Similar technique of ADSC enrichment of implanted adipose tissue was used for corrective treatment after artificial breast implants removal caused by various complications (like capsular contracture), and the results were described as satisfactory [185]. As a support and a carrier for transplanted ADSCs, “injectable scaffolds” consisting of cell-binding polyglycolic acid (PGA) [14], poly (lactic-co-glycolic acid) or PLGA [127], hyaluronic acid [49], fibrin [149], matrigel [76], or alginate gel [182] are applied. The in vivo study has shown that ADSCs attached to micronized acellular dermal matrix (Alloderm) and cultured for 14 days in adipogenic differentiation media were able to differentiate into mature adipocytes when implanted subcutaneously into dorsal cranial region of nude mice [183]. For the applications, when the elastic, mechanically resistant, non-immunogenic, and slow degradable scaffold is needed, 3-D scaffolds of silk fibroin were developed [106]. Interesting, although not yet validated, is the exploitation of the ability of ADSC to produce a variety of growth factors, regulatory factors, and collagen for skin antiaging therapy [126].
Bone Formation
The bone formation phenomenon was observed prior to the experiments with ADSC differentiation, in patients with progressive osseous heteroplasia, which is characterized by spontaneous formation of calcified nodules in the adipose tissue [72, 154]. In vitro, both human and animal ADSCs may be stimulated to differentiate into osteogenic lineage [28, 51, 144, 151, 187, 188], producing cells of osteogenic phenotype characterized by the presence of bone markers: alkaline phosphatase, osteopontin, osteonectin, type I collagen, bone sialoprotein, osteocalcin, BMP-2, BMP-4, and BMP receptors I and II. In vivo ADSCs differentiate into the bone when implanted ectopically into rodents [55]: rat-isolated ADSCs, seeded in polyglycolic acid, form the bone when implanted subcutaneously [89]. Similarly, human ADSCs in HA-TCP scaffolds differentiate to osteocytes in immunodeficient mice [31, 33]. ADSCs, when seeded in apatite-coated PLGA scaffolds and surgically implanted, were able to repair surgically created critical-size calvarial defects in mice [20]. In contrary to these observations, poly-L-lactic scaffolds colonized with non-differentiated ADSCs were unable to repair experimental rat palatal bone defects, while similar implants containing osteogenically differentiated cells fully reconstructed the bone defects in vivo [17]. Basing on these in vivo experiments, ADSCs were collected from a 7-year-old girl with large, bilateral calvarial defect, combined with iliac crest bone fragments and fibrin glue on resorbable mesh, and autologously implanted, treatment resulting in marked ossification and regeneration of defect to near-complete continuity after 3 months following surgery [92].
Cardiac Repair and Angiogenesis
Morbidity and mortality, resulting from cardiovascular diseases (CVDs), account for approximately 30 % causes of deaths, constituting major medical, social, and economical problem. At the beginning, the rationale of stem cell therapy of cardiac infarct was to implant cells, which will be able to transdifferentiate into cardiomyocytes and regenerate the necrotic region of the cardiac muscle. The obvious candidates, according to the cell plasticity concept, were hematopoietic stem cells from the bone marrow or umbilical cord blood. The effects observed in animal experiments were the increase of muscle mass in regenerating heart muscle, improvement of cardiac hemodynamics, and, surprisingly, very low frequency of the presence of myocardial cells of donor origin. Detection in the adipose tissue of the MSC-type cells capable of myogenic differentiation resulted in in vivo experiments based on intracardiac transplantation of ADSC in models of coronary disease or myocardial infarction [170]. It has to be determined, if the beneficial effects of treatment with ADSC results from differentiation of ADSC into myocardium or in paracrine mechanisms supporting endocrine repair [11, 13, 109, 119, 134, 156, 158, 169]. In 2004 the cardiomyogenic potential of ADSC has been documented [130, 175]; since then multiple studies have confirmed the phenomenon of direct formation of cardiac muscle by ADSCs [111, 173, 186]. It has been shown [100, 179] that the brown adipose is the best source of cells capable of cardiomyocyte differentiation. Treatment with ADSCs significantly improves functional parameters of regenerating heart, such as neovascularization [12, 13, 109, 130, 186], collateral perfusion [66, 67], and hemodynamic parameters (ventricular end-diastolic dimension, ejection fraction, cardiac output) [22, 107, 148, 169, 173]. ADSC transplantation into the heart does not increase arrhythmogenic tendency of the cardiac muscle [39, 73]. Some improvements may result from secretion humoral factors (angiogenic cytokines) by ADSC [134] or direct formation of endothelium and, in consequence, angiogenesis [12, 13].
The same mechanisms allow using ADSC for treatment of animal model of severe hind limb ischemia [119, 134]. Considering the importance of treatment of cardiac ischemia and infarct and the beneficial effects of ADSC on cardiac muscle regeneration, there is a real possibility of expanding the role of autologous ADSC in cardiac muscle regeneration and treatment of diseases with ischemic background.
Cartilage Repair
In general, the diseases originating from cartilage defect, resulting from injury, autoimmunity, or degenerative disease (osteoarthritis), have strong negative impact both at the patient’s level and at the social and economical levels. There have been published several attempts of inducing of cartilage repair using autologous stem and progenitor cells. In young patients with isolated cartilage lesions, the use of culture-expanded autologous chondrocytes seems most promising. In elderly patients, suffering from the massive denudation of articular cartilage, the availability of autologous expanded chondrocytes is, however, reduced and insufficient for therapy, so there is demand for another autologous cell source. The candidate cells must be available in adult donor, and their collection must be safe and relatively uncomplicated; these cells must have the potential for differentiation into chondrogenic lineage both in vitro and in vivo. Such cells must be also available in patients with osteochondral defects, so the original disease must not influence the numbers and qualities of cells collected for treatment. The candidate cells, fulfilling the criteria, are ADSCs collected from patient’s adipose tissue [120]. Comparison of the chondrogenic potential of BM-MSCs and ADSCs isolated from various locations confirmed that all these cells are able to differentiate into chondrocytes in vitro, but their differentiation potential depends on the source [113, 171, 177]. Some authors claim the superiority of ADSC over BM-MSC [24], but prevailing data suggest that BM-MSCs have superior chondrogenic potential when compared with ADSC [16, 59, 61, 85, 99, 126, 135, 150, 175]. The exception is intrapatellar fat pad, which is a much better cell source than subcutaneous adipose tissue [34, 113]. The future of ADSC as a candidate for cellular repair of cartilage is unclear; some findings suggest that improvement in in vitro/in vivo stimulation of chondrogenic differentiation of ADSC may increase their importance as candidates for clinical applications [36, 78].
Central Nervous System Repair and Regeneration
Limited natural capacity of self-renewal of neural system, combined with high frequency of accidents and diseases resulting in neural system dysfunction, emphasizes the importance of development of the new methods for stem cell application in neurological disorders. ADSC is capable of differentiating into neuropoietic lineage as well as regulating the neural repair and restoration of local circulation in central nervous system. Several authors documented that ADSCs are able to differentiate in vitro into neural cells [32, 60, 64, 71, 99, 181, 187], interact with neural cells on paracrine level [68], or produce Schwann-type cells [178]. There exists no evidence that adipose-derived cells, differentiating into neural cells, derive from the neural crest lineage [176].
There is also, unfortunately, no evidence that so-called neural cells observed in vitro are indeed mature functional neural cells – most authors recognize cells of “neural morphology” after identification selected markers present on early neural cells, like microtubule-associated protein, neuronal nuclear antigen, β-tubulin III [60], neurofilament 1 (NF1), nestin, neuron-specific enolase (NSE) [181], or neurosphere formation [71]. The other data derive from in vivo animal experiments, where ADSCs are implanted into regions of injury of neural system. The intensively researched problem is the possibility of amelioration of brain stroke effects by local application of ADSCs. Possible therapeutic effects may result from direct replacement of ischemia-eliminated brain cells, regulation of neural cell regeneration in paracrine manner, or reconstitution of local microcirculation by angiogenesis mediated or formed by ADSCs. When human ADSCs were injected into lateral ventricle of healthy rats, they were able to migrate to multiple areas including the contralateral cortex and could be locally identified up to 30 days following implantation. Similar implantation of ADSCs into the brain 1 day after MCA occlusion (the experimental model of stroke) resulted in cell migration into the ischemic area and localization at the border between the intact and injured brain tissue [69]. Injection of ADSCs did not change the infarct size but significantly improved the recovery in motor and somatosensory behavior aspects, suggesting that at least there exists the mechanism of local trophic support from ADSCs [69]. In other experiment, ADSCs not only improved neurological functions of infarcted rats but also markedly attenuated brain infarct size [93]. Immunomodulatory effect of ADSCs was exploited in the compassionate study on three patients with multiple sclerosis (the disease caused by the autoimmunity mechanisms). Multiple intravenous or intrathecal infusions of autologous ADSCs, combined with allogeneic CD34+ and MSCs, resulted in marked improvement in disease status of all patients, although the observation is very preliminary and statistically not significant [136]. ADSCs were tested for their ability to accelerate the spinal cord fusion (treatment for lumbar compression fractures) in rat model. Local application of scaffolds colonized by autologous or allogeneic ADSCs into the injury site reduced inflammatory cell infiltration and accelerated posterior spinal fusion process [102]. ADSC may act through the different mechanisms, like local regulation by paracrine manner [80, 94], participation in local angiogenesis, or immunomodulatory effects; the phenomenon of direct ADSCs differentiation to neural cells cannot also be excluded. Nevertheless of the mechanisms of ADSC actions, the preliminary in vivo results suggest the usefulness of both autologous and allogeneic ADSCs in treatment of central nervous system diseases and injuries.
Other Therapeutical Applications of ADSC
Experimental and clinical applications of ADSC resemble those exploited earlier with the use of BM-MSC. ADSCs seem to be the cell population, which may be widely used for gene therapy. In autologous transplantation model, gene-transfected ADSC guarantees relatively high safety, and their reported ability to maintain stable telomere length [37, 62] and long proliferation time in in vitro systems guarantees long-term delivery of gene product. Parallel experiments with infection of both MSCs and ADSCs with E1A-deleted type 5 adenovirus constructs containing the BMP-2 (bone morphogenic protein-2) gene or the bacterial beta-galactosidase (lacZ) gene resulted in 55 % transduction efficiency for ADSC in comparison with 35 % efficiency for BM-MSC [31], which resulted in threefold higher expression of BMP2 protein by ADSCs than by BM-MSCs. Experiments on stability of lentiviral vector-transduced cells revealed the presence of transduced cells in culture over 100 days at transduction efficiency of 98 % [116].
There are rather scarce data on the differentiation of ADSC into several cells and tissues, like skeletal and smooth muscle, hepatocyte-like cells, or pancreas endocrine cells. When transplanted into mdx mice (murine model of Duchenne muscular dystrophy), ADSC helped to regenerate the muscle and induced expression of dystrophin [140], although their role in muscle repair is still rather unclear. In vitro, ADSC differentiates into cells of myogenic phenotype, resembling the characteristics of skeletal muscle, the process observed when ADSCs are directly contacting primary muscle cells [27, 90]. Observations of in vitro capacity of ADSC to differentiate into smooth muscle cells [1, 42, 65, 91] were clinically exploited in attempted urinary incontinence treatment and bladder reconstitution [63], with results not substantially different to those obtained when used BM-MSC. There exist a scarce data on hepatopoietic differentiation potential of ADSC. In vitro, ADSC cultures in the presence of HGF, OSM, and DMSO form cells of hepatocyte-like phenotype, expressing albumin and α-fetoprotein, capable to take up low-density lipoprotein and to produce urea [152]. Following these observations, ADSCs, intravenously injected into mice, were detected in injured liver, and their integration into the liver was augmented by partial hepatectomy [79]. Preliminary data confirm the ability of ADSC to differentiate into cells of pancreatic endocrine phenotype partially maintaining pancreatic endocrine cell functions. Following the stimulation with activin-A, extendin-4, HGF, and pentagastrin, cells expressed pancreatic endocrine transcription factor Isl-1; developmental transcription factors Pax-6, Ipf-1, Ngn-3; and expressed pancreatic hormones insulin, glucagon, and somatostatin [165]. The data are too preliminary and need to be extended and confirmed, but even now they give some hope for the use of ADSC for cell-based therapy for type 1 diabetes mellitus. There exist also several reports of preliminary results after ADSC treatment of such varying diseases as Crohn’s disease (occlusion of rectovaginal fistula) [43, 46], wound healing [95], erectile dysfunction [96], tissue engineering (bypass graft construction [29], production of skin substitutes [166]), or feeder layer for induced pluripotent stem cells (iPSCs) [159]. All these reported ADSC therapeutic applications have one common characteristic – they need much more research for data collection and validation before their potential usefulness may be evaluated.
Conclusions
The phenotype, functional characteristics, and differentiation potential of ADSC are enough similar to their BM-MSC counterparts to conclude that the differences between ADSC and MSC are not important in the aspects of their applications for cellular therapy. The advantages of ADSC over MSC lay in the possibility of collection of much larger numbers of cells without endangering patient’s health. The other advantage is higher purity of isolated ADSC population – bone marrow aspirates consist of much higher numbers of hematopoietic cells than MSCs, and the most efficient method of primitive BM-MSC isolation (bone grinding) is impossible to use when considering collection from living donor. The most promising clinical applications of ADSC, according to presently available data, are treatment of cardiac ischemia and myocardial infarction, central nervous system repair following accidents or stroke, treatment of immunology-related diseases (graft-versus-host disease, multiple sclerosis), and techniques of bone and joints replacement and repair using scaffolds seeded with ADSCs and their more differentiated progeny. In the esthetic medicine/plastic surgery, ADSCs are the “cells of choice” for corrections of irregularities in subcutaneous tissue distribution.
In general, availability of large numbers of autologous cells in any patient’s age, safe protocols of cell collection, in vitro expansion and differentiation, multilineage differentiation potential, and in vivo immunomodulatory capacity make ADSC the almost ideal cell type for cellular therapy, gene therapy, and regenerative medicine.
References
Abderrahim-Ferkoune A, Bezy O, Astri-Roques S, Elabd C, Ailhaud G, Amri EZ. Transdifferentiation of preadipose cells into smooth muscle-like cells: role of aortic carboxypeptidase-like protein. Exp Cell Res. 2004;293:219–28.
Ahmad J, Eaves 3rd FF, Rohrich RJ, Kenkel JM. The American Society for Aesthetic Plastic Surgery (ASAPS) survey: current trends in liposuction. Aesthet Surg J. 2011;1:214–24.
Al Khaldi A, Al Sabti H, Galipeau J, Lachapelle K. Therapeutic angiogenesis using autologous bone marrow stromal cells: improved blood flow in a chronic limb ischemia model. Ann Thorac Surg. 2003;75:204–9.
Ashjian PH, Elbarbary AS, Edmonds B, DeUgarte D, Zhu M, Zuk PA, Lorenz HP, Benhaim P, Hedrick MH. In vitro differentiation of human processed lipoaspirate cells into early neural progenitors. Plast Reconstr Surg. 2003;111:1922–31.
Aust L, Devlin B, Foster SJ, Halvorsen YD, Hicok K, du Laney T, Sen A, Willingmyre GD, Gimble JM. Yield of human adipose-derived adult stem cells from liposuction aspirates. Cytotherapy. 2004;6:7–14.
Banfi A, Bianchi G, Galotto M, Cancedda R, Quarto R. Bone marrow stromal damage after chemo/radiotherapy: occurrence, consequences and possibilities of treatment. Leuk Lymphoma. 2001;42:863–70.
Banfi A, Podesta M, Fazzuoli L, Sertoli MR, Venturini M, Santini G, Cancedda R, Quarto R. High-dose chemotherapy shows a dose-dependent toxicity to bone marrow osteoprogenitors: a mechanism for post-bone marrow transplantation osteopenia. Cancer. 2001;92:2419–28.
Bjorntorp P, Karlsson M, Pertoft H, Pettersson L, Sjostrom U, Smith J. Isolation and characterization of cells from rat adipose tissue developing into adipocytes. J Lipid Res. 1978;19:316–24.
Boquest AC, Shahdadfar A, Fronsdal K, Sigurjonsson O, Tunheim SH, Collas P, Brinchmann JE. Isolation and transcription profiling of purified uncultured human stromal stem cells: alteration of gene expression after in vitro cell culture. Mol Biol Cell. 2005;16:1131–41.
Bunnell BA, Flaat M, Gagliardi C, Patel B, Ripoll C. Adipose-derived stem cells: isolation, expansion and differentiation. Methods. 2008;45:115–20.
Cai L, Johnstone BH, Cook TG, Liang Z, Traktuev D, Cornetta K, Ingram DA, Rosen ED, March KL. Suppression of hepatocyte growth factor production impairs the ability of adipose-derived stem cells to promote ischemic tissue revascularization. Stem Cells. 2007;25:3234–43.
Cai L, Johnstone BH, Cook TG, Tan J, Fishbein MC, Chen P-S, March KL. IFATS collection: human adipose tissue-derived stem cells induce angiogenesis and nerve sprouting following myocardial infarction, in conjunction with potent preservation of cardiac function. Stem Cells. 2009;27:230–7.
Cao Y, Sun Z, Liao L, Meng Y, Han Q, Zhao RC. Human adipose tissue-derived stem cells differentiate into endothelial cells in vitro and improve postnatal neovascularization in vivo. Biochem Biophys Res Commun. 2005;332:370–9.
Cho SW, Kim SS, Rhie JW, Cho HM, Choi CY, Kim BS. Engineering of volume-stable adipose tissues. Biomaterials. 2005;26:3577–85.
Cho YH, Bae YC, Jung JS. Role of Toll-like receptors on human adipose-derived stromal cells. Stem Cells. 2006;24:2744–52.
Colter DC, Sekiya I, Prockop DJ. Identification of a subpopulation of rapidly self-renewing and multipotential adult stem cells in colonies of human marrow stromal cells. Proc Natl Acad Sci U S A. 2001;98:7841–5.
Conejero JA, Lee JA, Parrett BM, Terry M, Wear-Maggitti K, Grant RT, Breitbart AS. Repair of palatal bone defects using osteogenically differentiated fat-derived stem cells. Plast Reconstr Surg. 2006;117:857–63.
Corre J, Barreau C, Cousin B, Chavoin JP, Caton D, Fournial G, Penicaud L, Casteilla L, Laharrague P. Human subcutaneous adipose cells support complete differentiation but not self-renewal of hematopoietic progenitors. J Cell Physiol. 2006;208:282–8.
Cousin B, Andre M, Arnaud E, Penicaud L, Casteilla L. Reconstitution of lethally irradiated mice by cells isolated from adipose tissue. Biochem Biophys Res Commun. 2003;301:1016–22.
Cowan CM, Shi YY, Aalami OO, Chou YF, Mari C, Thomas R, Quarto N, Contag CH, Wu B, Longaker MT. Adipose-derived adult stromal cells heal critical-size mouse calvarial defects. Nat Biotechnol. 2004;22:560–7.
D’Ippolito G, Schiller PC, Ricordi C, Roos BA, Howard GA. Age-related osteogenic potential of mesenchymal stromal stem cells from human vertebral bone marrow. J Bone Miner Res. 1999;14:1115–22.
Danoviz ME, Nakamuta JS, Fabio LN, Marques FLN, dos Santos L, Alvarenga EC, dos Santos AA, Ednei L, Antonio EL, Isolmar T, Schettert IT, Paulo J, Tucci PJ, Krieger JE. Rat adipose tissue-derived stem cells transplantation attenuates cardiac dysfunction post infarction and biopolymers enhance cell retention. PLoS One. 2010;5:e12077.
De Ugarte DA, Alfonso Z, Zuk PA, Elbarbary A, Zhu M, Ashjian P, Benhaim P, Hedrick MH, Fraser JK. Differential expression of stem cell mobilization-associated molecules on multi-lineage cells from adipose tissue and bone marrow. Immunol Lett. 2003;89:267–70.
De Ugarte DA, Morizono K, Elbarbary A, Alfonso Z, Zuk PA, Zhu M, Dragoo JL, Ashjian P, Thomas B, Benhaim P, Chen I, Fraser J, Hedrick MH. Comparison of multi-lineage cells from human adipose tissue and bone marrow. Cells Tissues Organs. 2003;174:101–9.
Delany J, Floyd ZE, Zvonic S, Smith A, Gravois A, Reiners E, Wu X, Kilroy G, Lefevre M, Gimble JM. Proteomic analysis of primary cultures of human adipose derived stem cells: modulation by adipogenesis. Mol Cell Proteomics. 2005;4:731–40.
Dennis JE, Carbillet JP, Caplan A, Charbord P. The STRO-1β marrow cell population is multipotential. Cells Tissues Organs. 2002;170:73–82.
Di Rocco G, Iachininoto MG, Tritarelli A, Straino S, Zacheo A, Germani A, Crea F, Capogrossi MC. Myogenic potential of adipose-tissue-derived cells. J Cell Sci. 2006;119:2945–52.
Dicker A, Le Blanc K, Astrom G, van Harmelen V, Götherström C, Blomqvist L, Arner P, Ryden M. Functional studies of mesenchymal stem cells derived from adult human adipose tissue. Exp Cell Res. 2005;308:283–90.
DiMuzio P, Tulenko. Tissue engineering applications to vascular bypass graft development: the use of adipose-derived stem cells. J Vasc Surg. 2007;45:99–103.
Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop DJ, Horwitz E. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8:315–7.
Dragoo JL, Choi JY, Lieberman JR, Huang J, Zuk PA, Zhang J, Hendrick MH, Benhaim P. Bone induction by BMP-2 transduced stem cells derived from human fat. J Orthop Res. 2003;21:622–9.
Dragoo JL, Samimi B, Zhu M, Hame SL, Thomas BJ, Lieberman JR, Hedrick MH, Benhaim P. Tissue-engineered cartilage and bone using stem cells from human infrapatellar fat pads. J Bone Joint Surg Br. 2003;85:740–7.
Dragoo JL, Lieberman JR, Lee RS, Deugarte DA, Lee Y, Zuk PA, Hedrick MH, Benhaim P. Tissue-engineered bone from BMP-2-transduced stem cells derived from human fat. Plast Reconstr Surg. 2005;115:1665–73.
English A, Jones EA, Corscadden D, Henshaw K, Chapman T, Emery P, McGonagle D. A comparative assessment of cartilage and joint fat pad as a potential source of cells for autologous therapy development in knee osteoarthritis. Rheumatology. 2007;46:1676–83.
Erickson GR, Gimble JM, Franklin DM, Rice HE, Awad H, Guilak F. Chondrogenic potential of adipose tissue-derived stromal cells in vitro and in vivo. Biochem Biophys Res Commun. 2002;290:763–9.
Estes BT, Wu AW, Guilak F. Potent induction of chondrocytic differentiation of human adipose-derived adult stem cells by bone morphogenetic protein 6. Arthritis Rheum. 2006;54:1222–32.
Estes BT, Wu AW, Storms RW, Guilak F. Extended passaging, but not aldehyde dehydrogenase activity, increases the chondrogenic potential of human adipose-derived adult stem cells. J Cell Physiol. 2006;209:987–95.
Fang B, Song YP, Liao LM, Han Q, Zhao RC. Treatment of severe therapy-resistant acute graft-versus-host disease with human adipose tissue-derived mesenchymal stem cells. Bone Marrow Transplant. 2006;38:389–90.
Fotuhi P, Song Y-H, Alt E. Electrophysiological consequence of adipose-derived stem cell transplantation in infarcted porcine myocardium. Europace. 2007;9:1218–21.
Fraser JK, Wulur I, Alfonso Z, Hedrick MH. Fat tissue: an underappreciated source of stem cells for biotechnology. Trends Biotechnol. 2006;24:150–4.
Gaben-Cogneville AM, Aron Y, Idriss G, Jahchan T, Pello JY, Swierczewski E. Differentiation under the control of insulin of rat preadipocytes in primary culture. Isolation of homogeneous cellular fractions by gradient centrifugation. Biochim Biophys Acta. 1983;762:437–44.
Gagnon A, Abaiian KJ, Crapper T, Layne MD, Sorisky A. Down-regulation of aortic carboxypeptidase-like protein during the early phase of 3 t3–l1 adipogenesis. Endocrinology. 2002;143:2478–85.
Garcia-Olmo D, Herreros D, De-La-Quintana P, Guadalajara H, Trebol J, Georgiev-Hristov T, Garcıa-Arranz M. Adipose-derived stem cells in Crohn’s rectovaginal fistula. Case Rep Med. 2010;2010:961758.
Gaustad KG, Boquest AC, Anderson BE, Gerdes AM, Collas P. Differentiation of human adipose tissue stem cells using extracts of rat cardiomyocytes. Biochem Biophys Res Commun. 2004;314:420–7.
Glick JM, Adelman SJ. Established cell lines from rat adipose tissue that secrete lipoprotein lipase. In Vitro. 1983;19:421–8.
Gonzalez-Rey E, Anderson P, Gonzalez MA, Rico L, Buscher D, Delgado M. Human adult stem cells derived from adipose tissue protect against experimental colitis and sepsis. Gut. 2009;58:929–39.
Gronthos S, Franklin DM, Leddy HA, Robey PG, Storms RW, Gimble JM. Surface protein characterization of human adipose tissue-derived stromal cells. J Cell Physiol. 2001;189:54–63.
Gronthos S, Graves SE, Ohta S, Simmons PJ. The STRO-1þ fraction of adult human bone marrow contains the osteogenic precursors. Blood. 1994;84:4164–73.
Halbleib M, Skurk T, de Luca C, von Heimburg D, Hauner H. Tissue engineering of white adipose tissue using hyaluronic acid-based scaffolds. I: in vitro differentiation of human adipocyte precursor cells on scaffolds. Biomaterials. 2003;24:3125–32.
Halvorsen YC, Wilkison WO, Gimble JM. Adipose-derived stromal cells – their utility and potential in bone formation. Int J Obes Relat Metab Disord. 2000;24:S41–4.
Halvorsen YD, Bond A, Sen A, Franklin DM, Lea-Currie YR, Sujkowski D, Ellis PN, Wilkison WO, Gimble JM. Thiazolidinediones and glucocorticoids synergistically induce differentiation of human adipose tissue stromal cells: biochemical, cellular, and molecular analysis. Metabolism. 2001;50:407–13.
Halvorsen YD, Franklin D, Bond AL, Hitt DC, Auchter C, Boskey AL, Paschalis EP, Wilkison WO, Gimble JM. Extracellular matrix mineralization and osteoblast gene expression by human adipose tissue-derived stromal cells. Tissue Eng. 2001;7:729–41.
Hattori H, Sato M, Masuoka K, Ishihara M, Kikuchi T, Matsui T, Takase B, Ishizuka T, Kikuchi M, Fujikawa K, Ishihara M. Osteogenic potential of human adipose tissue-derived stromal cells as an alternative stem cell source. Cells Tissues Organs. 2004;178:2–12.
Hauner HG, Entenmann M, Wabitsch D, Gaillard G, Ailhaud R, Negrel EF, Pfeiffer J. Promoting effect of glucocorticoids on the differentiation of human adipocyte precursor cells cultured in a chemically defined medium. J Clin Invest. 1989;84:1663–70.
Hicok KC, Du Laney TV, Zhou YS, Halvorsen YD, Hitt DC, Cooper LF, Gimble JM. Human adipose-derived adult stem cells produce osteoid in vivo. Tissue Eng. 2004;10:371–80.
Hollenberg CH, Vost A. Regulation of DNA synthesis in fat cells and stromal elements from rat adipose tissue. J Clin Invest. 1969;47:2485–98.
Horwitz EM, Le Blanc K, Dominici M, Mueller I, Slaper-Cortenbach I, Marini FC, Deans RJ, Krause DS, Keating A. Position paper. Clarification of the nomenclature for MSC: the International Society for Cellular Therapy position statement. Cytotherapy. 2005;7:393–5.
Huang JI, Beanes SR, Zhu M, Lorenz HP, Hedrick MH, Benhaim P. Rat extramedullary adipose tissue as a source of osteochondrogenic progenitor cells. Plast Reconstr Surg. 2002;109:1033–41.
Huang JI, Kazmi N, Durbhakula MM, Hering TM, Yoo JU, Johnstone B. Chondrogenic potential of progenitor cells derived from human bone marrow and adipose tissue: a patient- matched comparison. J Orthop Res. 2005;23:1383–9.
Huang T, He D, Kleiner G, Kuluz J. Neuron-like differentiation of adipose-derived stem cells from infant piglets in vitro. J Spinal Cord Med. 2007;30:S35–40.
Im G-I. Chondrogenesis from mesenchymal stem cells derived from adipose tissue on the fibrin scaffold. Curr Appl Phys. 2005;5:438–43.
Izadpanah R, Trygg C, Patel B, Kriedt C, Dufour J, Gimble JM, Bunnell BA. Biologic properties of mesenchymal stem cells derived from bone marrow and adipose tissue. J Cell Biochem. 2006;99:1286–97.
Jack GS, Almeida FG, Zhang R, Alfonso ZC, Zuk PA, Rodriguez LV. Processed lipoaspirate cells for tissue engineering of the lower urinary tract: implications for the treatment of stress urinary incontinence and bladder reconstruction. J Urol. 2005;174:2041–5.
Jang S, Cho HH, Cho YB, Park JS, Jeong HS. Functional neural differentiation of human adipose tissue-derived stem cells using bFGF and forskolin. BMC Cell Biol. 2010;11:25.
Jeon ES, Moon HJ, Lee MJ, Song HY, Kim YM, Bae YC, Jung JS, Kim JH. Sphingosylphosphorylcholine induces differentiation of human mesenchymal stem cells into smooth-muscle-like cells through a tgf-β-dependent mechanism. J Cell Sci. 2006;119:4994–5005.
Kamihata H, Matsubara H, Nishiue T, Fujiyama S, Tsutsumi Y, Ozono R, Masaki H, Mori Y, Iba O, Tateishi E, Kosaki A, Shintani S, Murohara T, Imaizumi T, Iwasaka T. Implantation of bone marrow mononuclear cells into ischemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands, and cytokines. Circulation. 2001;104:1046–52.
Kamihata H, Matsubara H, Nishiue T, Fujiyama S, Amano K, Iba O, Imada T, Iwasaka T. Improvement of collateral perfusion and regional function by implantation of peripheral blood mononuclear cells into ischemic hibernating myocardium. Arterioscler Thromb Vasc Biol. 2002;22:1804–10.
Kang SK, Jun ES, Bae YC, Jung JS. Interactions between human adipose stromal cells and mouse neural stem cells in vitro. Brain Res Dev Brain Res. 2003;145:141–9.
Kang SK, Lee DH, Bae YC, Kim HK, Baik SY, Jung JS. Improvement of neurological deficits by intracerebral transplantation of human adipose tissue-derived stromal cells after cerebral ischemia in rats. Exp Neurol. 2003;183:355–66.
Kang SK, Putnam L, Dufour J, Ylostalo J, Jung JS, Bunnell BA. Expression of telomerase extends the lifespan and enhances osteogenic differentiation of adipose tissue-derived stromal cells. Stem Cells. 2004;22:1356–72.
Kang SK, Putnam LA, Ylostalo J, Popescu IR, Dufour J, Belousov A, Bunnell BA. Neurogenesis of rhesus adipose stromal cells. J Cell Sci. 2004;117:4289–99.
Kaplan FS, Hahn GV, Zasloff MA. Heterotopic ossification: two rare forms and what they can teach us. J Am Acad Orthop Surg. 1994;2:288–96.
Katritsis DG, Sotiropoulou P, Giazitzoglou E, Karvouni E, Papamichail M. Electrophysiological effects of intracoronary transplantation of autologous mesenchymal and endothelial progenitor cells. Europace. 2007;9:167–71.
Katz AJ, Hedrick MH, Llull R, Futrell JW. A novel device for the simple and efficient refinement of liposuctioned tissue. Plast Reconstr Surg. 2001;107:595–7.
Katz AJ, Tholpady A, Tholpady SS, Shang H, Ogle RC. Cell surface and transcriptional characterization of human adipose-derived adherent stromal (hadas) cells. Stem Cells. 2005;23:412–23.
Kawaguchi N, Toriyama K, Nicodemou-Lena E, Inou K, Torii S, Kitagawa Y. De novo adipogenesis in mice at the site of injection of basement membrane and basic fibroblast growth factor. Proc Natl Acad Sci U S A. 1998;95:1062–6.
Kern S, Eichler H, Stoeve J, Kluter H, Bieback K. Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells. 2006;24:1294–301.
Khan WS, Tew SR, Adesida AB, Hardingham TE. Human infrapatellar fat pad-derived stem cells express the pericyte marker 3G5 and show enhanced chondrogenesis after expansion in fibroblast growth factor-2. Arthritis Res Ther. 2008;10:R74.
Kim DH, Je CM, Sin JY, Jung JS. Effect of partial hepatectomy on in vivo engraftment after intravenous administration of human adipose tissue stromal cells in mouse. Microsurgery. 2003;23:424–31.
Kinnaird T, Stabile E, Burnett MS, Lee CW, Barr S, Fuchs S, Epstein SE. Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. Circ Res. 2004;94:678–85.
Klein JA. The tumescent technique. Anesthesia and modified liposuction technique. Dermatol Clin. 1990;8:425–37.
Knippenberg M, Helder MN, Doulabi BZ, Semeins CM, Wuisman PI, Klein-Nulend J. Adipose tissue-derived mesenchymal stem cells acquire bone cell-like responsiveness to fluid shear stress on osteogenic stimulation. Tissue Eng. 2005;11:1780–8.
Knippenberg M, Helder MN, Doulabi BZ, Bank RA, Wuisman PI, Klein-Nulend J. Differential effects of bone morphogenetic protein-2 and transforming growth factor-beta1 on gene expression of collagen-modifying enzymes in human adipose tissue-derived mesenchymal stem cells. Tissue Eng Part A. 2009;15:2213–25.
Koc ON, Gerson SL, Cooper BW, Dyhouse SM, Haynesworth SE, Caplan AI, Lazarus HM. Rapid hematopoietic recovery after coinfusion of autologous-blood stem cells and culture- expanded marrow mesenchymal stem cells in advanced breast cancer patients receiving high-dose chemotherapy. J Clin Oncol. 2000;18:307–16.
Koga H, Muneta T, Nagase T, Nimura A, Ju YJ, Mochizuki T, Sekiya I. Comparison of mesenchymal tissues-derived stem cells for in vivo chondrogenesis: suitable conditions for cell therapy of cartilage defects in rabbit. Cell Tissue Res. 2008;333:207–15.
Krampera M, Marconi S, Pasini A, Galie M, Rigotti G, Mosna F, Tinelli M, Lovato L, Anghileri E, Andreini A, Pizzolo G, Sbarbati A, Bonetti B. Induction of neural-like differentiation in human mesenchymal stem cells derived from bone marrow, fat, spleen and thymus. Bone. 2007;40:382–90.
Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I, Lanino E, Sundberg B, Bernardo ME, Remberger M, Dini G, Egeler RM, Bacigalupo A, Fibbe W, Ringdén O. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet. 2008;371:1579–86.
Lecoeur L, Ouhayoun JP. In vitro induction of osteogenic differentiation from non-osteogenic mesenchymal cells. Biomaterials. 1997;18:989–93.
Lee JA, Parrett BM, Conejero JA, Laser J, Chen J, Kogon AJ, Nanda D, Grant RT, Breitbart AS. Biological alchemy: engineering bone and fat from fat-derived stem cells. Ann Plast Surg. 2003;50:610–7.
Lee JH, Kemp DM. Human adipose-derived stem cells display myogenic potential and perturbed function in hypoxic conditions. Biochem Biophys Res Commun. 2006;341:882–8.
Lee WC, Rubin JP, Marra KG. Regulation of alpha-smooth muscle actin protein expression in adipose-derived stem cells. Cells Tissues Organs. 2006;183:80–6.
Lendeckel S, Jodicke A, Christophis P, Heidinger K, Wolff J, Fraser JK, Hedrick MH, Berthold L, Howaldt HP. Autologous stem cells (adipose) and fibrin glue used to treat widespread traumatic calvarial defects: case report. J Craniomaxillofac Surg. 2004;32:370–3.
Leu S, Lin YC, Yuen CM, Yen CH, Kao YS, Cheuk-Kwan Sun CK, Yip HK. Adipose-derived mesenchymal stem cells markedly attenuate brain infarct size and improve neurological function in rats. J Transl Med. 2010;8:63.
Li TS, Ito H, Hayashi M, Furutani A, Matsuzaki M, Hamano K. Cellular expression of integrin-beta(1) is of critical importance for inducing therapeutic angiogenesis by cell implantation. Cardiovasc Res. 2005;65:64–72.
Lim JS, Yoo G. Effects of adipose-derived stromal cells and of their extract on wound healing in a mouse model. J Korean Med Sci. 2010;25:746–51.
Lin G, Banie L, Ning H, Bella AJ, Lin CS, Lue TF. Potential of adipose-derived stem cells for treatment of erectile dysfunction. J Sex Med. 2009;6:320–7.
Lin G, Yang R, Banie L, Wang G, Ning H, Li LC, Lue TF, Lin CS. Effects of transplantation of adipose tissue-derived stem cells on prostate tumor. Prostate. 2010;70:1066–73.
Lin K, Matsubara Y, Masuda Y, Togashi K, Ohno T, Tamura T, Toyoshima Y, Sugimachi K, Toyoda M, Marc H, Douglas A. Characterization of adipose tissue-derived cells isolated with the CelutionTM system. Cytotherapy. 2008;10:417–26.
Liu TM, Martina M, Hutmacher DW, Hui JH, Lee EH, Lim B. Identification of common pathways mediating differentiation of bone marrow- and adipose tissue-derived human mesenchymal stem cells into three mesenchymal lineages. Stem Cells. 2007;25:750–60.
Liu Z, Wang H, Zhang Y, Zhou J, Lin Q, Wang Y, Duan C, Wu K, Wang C. Efficient isolation of cardiac stem cells from brown adipose. J Biomed Biotechnol. 2010;2010. 104296.
Lohsiriwat V, Curigliano G, Rietjens M, Goldhirsch A, Petit J. Autologous fat transplantation in patients with breast cancer: “silencing” or “fueling” cancer recurrence? Breast. 2011;20(4):351–7.
Lopez MJ, McIntosh KR, Spencer ND, Borneman JN, Horswell R, Anderson P, Yu G, Gaschen L, Gimble JM. Acceleration of spinal fusion using syngeneic and allogeneic adult adipose derived stem cells in a rat model. J Orthop Res. 2009;27:366–73.
Majumdar MK, Thiede MA, Mosca JD, Moorman M, Gerson SL. Phenotypic and functional comparison of cultures of marrow-derived mesenchymal stem cells (MSCs) and stromal cells. J Cell Physiol. 1998;176:57–66.
Martin RJ, Hausman GJ, Hausman DB. Regulation of adipose cell development in utero. Proc Soc Exp Biol Med. 1998;219:200–10.
Matsumoto D, Sato K, Gonda K, Takaki Y, Shigeura T, Sato T, Aiba-Kojima E, Iizuka F, Inoue K, Suga H, Yoshimura K. Cell-assisted lipotransfer: supportive use of human adipose-derived cells for soft tissue augmentation with lipoinjection. Tissue Eng. 2006;12:3375–82.
Mauney JR, Nguyen T, Gillen K, Kirker-Head C, Gimble JM, Kaplan DL. Engineering adipose-like tissue in vitro and in vivo utilizing human bone marrow and adipose-derived mesenchymal stem cells with silk fibroin 3D scaffolds. Biomaterials. 2007;28:5280–90.
Mazo M, Planat-Benard V, Abizanda G, Pelacho B, Leobon B, et al. Transplantation of adipose derived stromal cells is associated with functional improvement in a rat model of chronic myocardial infarction. Eur J Heart Fail. 2008;10:454–62.
McIntosh K, Zvonic S, Garrett S, Mitchell JB, Floyd ZE, Hammill L, Kloster A, Halvorsen YD, Ting JP, Storms RW, Goh B, Kilroy G, Wu X, Gimble JM. The immunogenicity of human adipose derived cells: temporal changes in vitro. Stem Cells. 2006;24:1245–53.
Miranville A, Heeschen C, Sengenes C, Curat CA, Busse R, Bouloumie A. Improvement of postnatal neovascularization by human adipose tissue-derived stem cells. Circulation. 2004;110:349–55.
Mitchell JB, McIntosh K, Zvonic S, Garrett S, Floyd ZE, Kloster A, Di Halvorsen Y, Storms RW, Goh B, Kilroy G, Wu X, Gimble JM. The immunophenotype of human adipose derived cells: temporal changes in stromal- and stem cell-associated markers. Stem Cells. 2006;24:376–85.
Miyahara Y, Nagaya N, Kataoka M, Yanagawa B, Tanaka K, Hao H, Ishino K, Ishida H, Shimizu T, Kangawa K, Sano S, Okano T, Kitamura S, Mori H. Monolayered mesenchymal stem cells repair scarred myocardium after myocardial infarction. Nat Med. 2006;12:459–65.
Mizuno H, Zuk PA, Zhu M, Lorenz HP, Benhaim P, Hedrick MH. Myogenic differentiation by human processed lipoaspirate cells. Plast Reconstr Surg. 2002;109:199–209.
Mochizuki T, Muneta T, Sakaguchi Y, Nimura A, Yokoyama A, Koga H, Sekiya I. Higher chondrogenic potential of fibrous synovium – and adipose synovium–derived cells compared with subcutaneous fat–derived cells. Distinguishing properties of mesenchymal stem cells in humans. Arthritis Rheum. 2006;54:843–53.
Momin EN, Vela G, Zaidi HA, Quiñones-Hinojosa A. The oncogenic potential of mesenchymal stem cells in the treatment of cancer: directions for future research. Curr Immunol Rev. 2010;6:137–48.
Moon MH, Kim SY, Kim YJ, Kim SJ, Lee JB, Bae YC, Sung SM, Jung JS. Human adipose tissue-derived mesenchymal stem cells improve postnatal neovascularization in a mouse model of hindlimb ischemia. Cell Physiol Biochem. 2006;17:279–90.
Morizono K, De Ugarte DA, Zhu M, Zuk P, Elbarbary A, Ashjian P, Benhaim P, Chen IS, Hedrick MH. Multilineage cells from adipose tissue as gene delivery vehicles. Hum Gene Ther. 2003;14:59–66.
Muehlbergy FL, Songy Y-H, Krohn A, Pinilla SP, Droll LH, Leng X, Seidensticker M, Ricke J, Altman AM, Devarajan E, Liu W, Arlinghaus RB, Alt EU. Tissue-resident stem cells promote breast cancer growth and metastasis. Carcinogenesis. 2009;30:589–97.
Muschler GF, Nitto H, Boehm CA, Easley KA. Age- and gender-related changes in the cellularity of human bone marrow and the prevalence of osteoblastic progenitors. J Orthop Res. 2001;19:117–25.
Nakagami H, Maeda K, Morishita R, Iguchi S, Nishikawa T, Takami Y, Kikuchi Y, Saito Y, Tamai K, Ogihara T, Kaneda Y. Novel autologous cell therapy in ischemic limb disease through growth factor secretion by cultured adipose tissue-derived stromal cells. Arterioscler Thromb Vasc Biol. 2005;25:2542–7.
Nathan S, Das DS, Thambyah A, Fen C, Goh J, Lee EH. Cell-based therapy in the repair of osteochondral defects: a novel use for adipose tissue. Tissue Eng. 2003;9:733–44.
Ning H, Liu G, Lin G, Garcia M, Li LC, Lue TF, Lin C-S. Identification of an aberrant cell line among human adipose tissue-derived stem cell isolates. Differentiation. 2009;77:172–80.
Nnodim JO. Development of adipose tissues. Anat Rec. 1987;219:331–7.
Oedayrajsingh-Varma MJ, van Ham SM, Knippenberg M, Helder MN, Klein-Nulend J, Schouten TE, Ritt MJ, van Milligen FJ. Adipose tissue-derived mesenchymal stem cell yield and growth characteristics are affected by the tissue-harvesting procedure. Cytotherapy. 2006;8:166–77.
Ogawa R, Mizuno H, Watanabe A, Migita M, Shimada T, Hyakusoku H. Osteogenic and chondrogenic differentiation by adipose-derived stem cells harvested from GFP transgenic mice. Biochem Biophys Res Commun. 2004;313:871–7.
Panetta NJ, Gupta DM, Kwan MD, Wan DC, Commons GW, Longaker MT. Tissue harvest by means of suction-assisted or third-generation ultrasound-assisted lipoaspiration has no effect on osteogenic potential of human adipose-derived stromal cells. Plast Reconstr Surg. 2009;124:65–73.
Park J, Gelse K, Frank S, von der Mark K, Aigner T, Schneider H. Transgene-activated mesenchymal cells for articular cartilage repair: a comparison of primary bone marrow-, perichondrium/periosteum- and fat-derived cells. J Gene Med. 2006;8:112–25.
Patrick Jr CW, Chauvin PB, Hobley J, Reece GP. Preadipocyte seeded PLGA scaffolds for adipose tissue engineering. Tissue Eng. 1999;5:139–51.
Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284:143–7.
Planat-Benard V, Menard C, Andre M, Puceat M, Perez A, Garcia-Verdugo JM, Penicaud L, Casteilla L. Spontaneous cardiomyocyte differentiation from adipose tissue stroma cells. Circ Res. 2004;94:223–9.
Planat-Benard V, Silvestre JS, Cousin B, Andre M, Nibbelink M, Tamarat R, Clergue M, Manneville C, Saillan-Barreau C, Duriez M, Tedgui A, Levy B, Penicaud L, Casteilla L. Plasticity of human adipose lineage cells toward endothelial cells: physiological and therapeutic perspectives. Circulation. 2004;109:656–63.
Pojda Z. Use of non-hematopoietic stem cells of fetal origin from cord blood, umbilical cord, and placenta in regeneration medicine. In: Bhattacharya N, Stubblefield P, editors. Regenerative medicine using pregnancy-specific biological substances. London: Springer; 2011.
Puissant B, Barreau C, Bourin P, Clavel C, Corre J, Bousquet C, Taureau C, Cousin B, Abbal M, Laharrague P, Penicaud L, Casteilla L, Blancher A. Immunomodulatory effect of human adipose tissue-derived adult stem cells: comparison with bone marrow mesenchymal stem cells. Br J Haematol. 2005;129:118–29.
Rangappa S, Fen C, Lee EH, Bongso A, Wei ES. Transformation of adult mesenchymal stem cells isolated from the fatty tissue into cardiomyocytes. Ann Thorac Surg. 2003;75:775–9.
Rehman J, Traktuev D, Li J, Merfeld-Clauss S, Temm-Grove CJ, Bovenkerk JE, Pell CL, Johnstone BH, Considine RV, March KL. Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells. Circulation. 2004;109:1292–8.
Rider DA, Dombrowski C, Sawyer AA, Ng GH, Leong D, Hutmacher DW, Nurcombe V, Cool SM. Autocrine fibroblast growth factor 2 increases the multipotentiality of human adipose-derived mesenchymal stem cells. Stem Cells. 2008;26:1598–608.
Riordan NH, Ichim TE, Min WP, Wang H, Solano F, Lara F, Alfaro M, Rodriguez JP, Harman RJ, Patel AN, Murphy MP, Lee RR, Minev B. Non-expanded adipose stromal vascular fraction cell therapy for multiple sclerosis. J Transl Med. 2009;7:29.
Rodbell M. Metabolism of isolated fat cells. II. The similar effects of phospholipase c (clostridium perfringens alpha toxin) and of insulin on glucose and amino acid metabolism. J Biol Chem. 1966;241:130–9.
Rodbell M. The metabolism of isolated fat cells. IV. Regulation of release of protein by lipolytic hormones and insulin. J Biol Chem. 1966;241:3909–17.
Rodbell M, Jones AB. Metabolism of isolated fat cells. III. The similar inhibitory action of phospholipase c (clostridium perfringens alpha toxin) and of insulin on lipolysis stimulated by lipolytic hormones and theophylline. J Biol Chem. 1966;241:140–2.
Rodriguez AM, Pisani D, Dechesne CA, Turc-Carel C, Kurzenne JY, Wdziekonski B, Villageois A, Bagnis C, Breittmayer JP, Groux H, Ailhaud G, Dani C. Transplantation of a multipotent cell population from human adipose tissue induces dystrophin expression in the immunocompetent mdx mouse. J Exp Med. 2005;201:1397–405.
Roebuck KA, Finnegan A. Regulation of intercellular adhesion molecule-1 (CD54) gene expression. J Leukoc Biol. 1999;66:876–88.
Romanov YA, Darevskaya AN, Merzlikina NV, Buravkova LB. Mesenchymal stem cells from human bone marrow and adipose tissue: isolation, characterization, and differentiation potentialities. Bull Exp Biol Med. 2005;140:138–43.
Rubio D, Garcia-Castro J, Martin MC, de la Fuente R, Cigudosa JC, Lloyd AC, Bernad A. Spontaneous human adult stem cell transformation. Cancer Res. 2005;65:3035–9.
Ryden M, Dicker A, Gotherstrom C, Astrom G, Tammik C, Arner P, Le Blanc K. Functional characterization of human mesenchymal stem cell-derived adipocytes. Biochem Biophys Res Commun. 2003;311:391–7.
Safford KM, Hicok KC, Safford SD, Halvorsen YD, Wilkison WO, Gimble JM, Rice HE. Neurogenic differentiation of murine and human adipose-derived stromal cells. Biochem Biophys Res Commun. 2002;294:371–9.
Safford KM, Safford SD, Gimble JM, Shetty AK, Rice HE. Characterization of neuronal/glial differentiation of murine adipose-derived adult stromal cells. Exp Neurol. 2004;187:319–28.
Safford KM, Rice HE. Stem cell therapy for neurologic disorders: therapeutic potential of adipose-derived stem cells. Curr Drug Targets. 2005;6:57–62.
Schenke-Layland K, Strem BM, Jordan MC, DeEmedio MT, Hedrick MH, Roos KP, Fraser JK, MacLellan WR. Adipose tissue-derived cells improve cardiac function following myocardial infarction. J Surg Res. 2009;153:217–23.
Schoeller T, Lille S, Wechselberger G, Otto A, Mowlavi A, Piza-Katzer H, Mowlawi A. Histomorphologic and volumetric analysis of implanted autologous preadipocyte cultures suspended in fibrin glue: a potential new source for tissue augmentation. Aesthetic Plast Surg. 2001;25:57–63.
Sekiya I, Larson BL, Smith JR, Pochampally R, Cui JG, Prockop DJ. Expansion of human adult stem cells from bone marrow stroma: conditions that maximize the yields of early progenitors and evaluate their quality. Stem Cells. 2002;20:530–41.
Sen A, Lea-Currie YR, Sujkowska D, Franklin DM, Wilkison WO, Halvorsen YD, Gimble JM. Adipogenic potential of human adipose derived stromal cells from multiple donors is heterogeneous. J Cell Biochem. 2001;81:312–9.
Seo MJ, Suh SY, Bae YC, Jung JS. Differentiation of human adipose stromal cells into hepatic lineage in vitro and in vivo. Biochem Biophys Res Commun. 2005;328:258–64.
Shi YY, Nacamuli RP, Salim A, Longaker MT. The osteogenic potential of adipose-derived mesenchymal cells is maintained with aging. Plast Reconstr Surg. 2005;116:1686–96.
Shore EM, Ahn J, Jan DB, Li M, Xu M, Gardner RJ, Zasloff MA, Whyte MP, Levine MA, Kaplan FS. Paternally inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia. N Engl J Med. 2002;346:99–106.
Simmons PJ, Gronthos S, Zannettino A, Ohta S, Graves S. Isolation, characterization and functional activity of human marrow stromal progenitors in hemopoiesis. Prog Clin Biol Res. 1994;389:271–80.
Song YH, Gehmert S, Sadat S, Pinkernell K, Bai X, Matthias N, Alt E. VEGF is critical for spontaneous differentiation of stem cells into cardiomyocytes. Biochem Biophys Res Commun. 2007;354:999–1003.
Strem BM, Hicok KC, Zhu M, Wulur I, Alfonso Z, Schreiber RE, Fraser JK, Hedrick MH. Multipotential differentiation of adipose tissue-derived stem cells. Keio J Med. 2005;54:132–41.
Strem BM, Zhu M, Alfonso Z, Daniels EJ, Schreiber R, Beygui R, MacLellan WR, Hedrick MH, Fraser JK. Expression of cardiomyocytic markers on adipose tissue-derived cells in a murine model of acute myocardial injury. Cytotherapy. 2005;7:282–91.
Sugii S, Kida Y, Kawamura T, Suzuki J, Vassena R, Yin YQ, Lutz MK, Berggren WT, Belmonte JCI, Evans RM. Human and mouse adipose-derived cells support feeder-independent induction of pluripotent stem cells. Proc Natl Acad Sci U S A. 2010;107:3558–63 [191].
Sumi M, Sata M, Toya N, Yanaga K, Ohki T, Nagai R. Transplantation of adipose stromal cells, but not mature adipocytes, augments ischemia-induced angiogenesis. Life Sci. 2007;80:559–65.
Sun HJ BY, Choi YR, Shim JH, Han SH, Lee YW. A proteomic analysis during serial subculture and osteogenic differentiation of human mesenchymal stem cell. J Orthop Res. 2006;24:2059–71. 43.
Talens-Visconti R, Bonora A, Jover R, Mirabet V, Carbonell F, Castell JV, Gomez-Lechon MJ. Hepatogenic differentiation of human mesenchymal stem cells from adipose tissue in comparison with bone marrow mesenchymal stem cells. World J Gastroenterol. 2006;12:5834–45.
Talens-Visconti R, Bonora A, Jover R, Mirabet V, Carbonell F, Castell JV, Gomez-Lechon MJ. Human mesenchymal stem cells from adipose tissue: differentiation into hepatic lineage. Toxicol In Vitro. 2007;21:324–9.
Tholpady SS, Katz AJ, Ogle RC. Mesenchymal stem cells from rat visceral fat exhibit multipotential differentiation in vitro. Anat Rec. 2003;272A:398–402.
Timper K, Seboek D, Eberhardt M, Linscheid P, Christ-Crain M, Keller U, Muller B, Zulewski H. Human adipose tissue-derived mesenchymal stem cells differentiate into insulin, somatostatin, and glucagon expressing cells. Biochem Biophys Res Commun. 2006;341:1135–40.
Troittier V, Marceau-Fortier G, Germain L, Vincent C, Fradette J. IFATS collection: using human adipose-derived stem/stromal cells for the production of new skin substitutes. Stem Cells. 2008;26:2713–23.
Urbich C, Dimmeler S. Endothelial progenitor cells functional characterization. Trends Cardiovasc Med. 2004;14:318–22.
Urbich C, Dimmeler S. Risk factors for coronary artery disease, circulating endothelial progenitor cells, and the role of HMG-CoA reductase inhibitors. Kidney Int. 2005;67:1672–6.
Valina C, Pinkernell K, Song Y-H, Bai X, Sadat S, Campeau RJ, Le Jemtel TH, Alt E. Intracoronary administration of autologous adipose tissue-derived stem cells improves left ventricular function, perfusion, and remodelling after acute myocardial infarction. Eur Heart J. 2007;28:2667–77.
van der Bogt KEA, Schrepfer S, Yu J, Sheikh AY, Hoyt G, Govaert JA, Velotta JB, Contag CH, Robbins RC, Wu JC. Comparison of transplantation of adipose tissue- and bone marrow-derived mesenchymal stem cells in the infarcted heart. Transplantation. 2009;87:642–52.
Vidal MA, Robinson SO, Lopez MJ, Paulsen DB, Borkhsenious O, Johnson JR, Moore RM, Gimble JM. Comparison of chondrogenic potential in equine mesenchymal stromal cells derived from adipose tissue and bone marrow. Vet Surg. 2008;37:713–24.
Wang D, Park JS, Chu JS, Krakowski A, Luo K, Chen DJ, Li S. Proteomic profiling of bone marrow mesenchymal stem cells upon transforming growth factor beta1 stimulation. J Biol Chem. 2004;279:43725–34.
Wang L, Deng J, Tian W, Xiang B, Yang T, et al. Adipose-derived stem cells are an effective cell candidate for treatment of heart failure: an MR imaging study of rat hearts. Am J Physiol Heart Circ Physiol. 2009;297:1020–31.
Wickham MQ, Erickson GR, Gimble JM, Vail TP, Guilak F. Multipotent stromal cells derived from the infrapatellar fat pad of the knee. Clin Orthop. 2003;412:196–212.
Winter A, Breit S, Parsch D, Benz K, Steck E, Hauner H, Weber RM, Ewerbeck V, Richter W. Cartilage-like gene expression in differentiated human stem cell spheroids: a comparison of bone marrow-derived and adipose tissue-derived stromal cells. Arthritis Rheum. 2003;48:418–29.
Wrage PC, Tran T, To K, Keefer EW, Ruhn KA, Hong J, Hattangadi S, Trevino I, Tansey MG. The neuro-glial properties of adipose-derived adult stromal (ADAS) cells are not regulated by Notch 1 and are not derived from neural crest lineage. PLoS One. 2008;3(1):e1453.
Xu Y, Balooch G, Chiou M, Bekerman E, Ritchie RO, Longaker MT. Analysis of the material properties of early chondrogenic differentiated adipose-derived stromal cells (ASC) using an in vitro three-dimensional micromass culture system. Biochem Biophys Res Commun. 2007;359:311–6.
Xu Y, Liu Z, Liu L, Zhao C, Xiong F, Zhou C, Li Y, Shan Y, Peng F, Zhang C. Neurospheres from rat adipose-derived stem cells could be induced into functional Schwann cell-like cells in vitro. BMC Neurosci. 2008;9:21.
Yamada Y, Wang XD, Yokoyama S, Fukuda N, Takakura N. Cardiac progenitor cells in brown adipose tissue repaired damaged myocardium. Biochem Biophys Res Commun. 2006;342:662–70.
Yanez R, Lamana ML, Garcia-Castro J, Colmenero I, Ramirez M, Bueren JA. Adipose tissue-derived mesenchymal stem cells have in vivo immunosuppressive properties applicable for the control of the graft-versus-host disease. Stem Cells. 2006;24:2582–91.
Yang LY, Liu XM, Sun B, Hui GZ, Fei J, Guo LH. Adipose tissue-derived stromal cells express neuronal phenotypes. Chin Med J (Engl). 2004;117:425–9.
Yoo G, Yea BH, Rhie JW, Kwon H, Wee SS, Ahn ST. Growth and differentiation of preadipocytes in alginate and collagen gels. J Kor Soc Plast Reconstr Surg. 2000;27:386–92.
Yoo G, Lim JS. Tissue engineering of injectable soft tissue filler: using adipose stem cells and micronized acellular dermal matrix. J Korean Med Sci. 2009;24:104–9.
Yoshimura K, Sato K, Aoi N, Kurita M, Hirohi T, Harii K. Cell-assisted lipotransfer for cosmetic breast augmentation: supportive use of adipose-derived stem/stromal cells. Aesthetic Plast Surg. 2008;32:48–55.
Yoshimura K, Asano Y, Aoi N, Kurita M, Oshima Y, Sato K, Inoue K, Suga H, Eto H, Kato H, Harii K. Progenitor-enriched adipose tissue transplantation as rescue for breast implant complications. Breast J. 2010;16:169–75.
Zhang DZ, Gai LY, Liu HW, Jin QH, Huang JH, Zhu XY. Transplantation of autologous adipose-derived stem cells ameliorates cardiac function in rabbits with myocardial infarction. Chin Med J (Engl). 2007;120:300–7.
Zuk PA, Zhu M, Ashjian P, De Ugarte DA, Huang JI, Mizuno H, Alfonso ZC, Fraser JK, Benhaim P, Hedrick MH. Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell. 2002;13:4279–95.
Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, Katz AJ, Benhaim P, Lorenz HP, Hedrick MH. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng. 2001;7:211–28.
Acknowledgments
Supported by the EC Innovative Economy Programme, Priority 1, Strategic Programme 1.1.2. “Bioimplants for the treatment of bone tissue lesions in oncological patients (Bio-Implant)”.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2015 Springer-Verlag London
About this chapter
Cite this chapter
Pojda, Z. (2015). Adipose-Derived Stem Cells for Therapeutic Applications. In: Bhattacharya, N., Stubblefield, P. (eds) Regenerative Medicine. Springer, London. https://doi.org/10.1007/978-1-4471-6542-2_9
Download citation
DOI: https://doi.org/10.1007/978-1-4471-6542-2_9
Published:
Publisher Name: Springer, London
Print ISBN: 978-1-4471-6541-5
Online ISBN: 978-1-4471-6542-2
eBook Packages: MedicineMedicine (R0)