Abstract
Acute kidney injury carries severe consequences and has limited treatment options. Bone marrow stem cells may offer the potential for treatment of acute kidney injury. The purpose of this review is twofold. The first purpose is to provide a concise overview of the biology of bone marrow stem cells, including hematopoietic stem cells and mesenchymal stem cells, for clinical nephrologists and renal researchers. The second purpose is to summarize published data regarding the role of bone marrow stem cells in renal repair after acute kidney injury. Currently, much of our knowledge of renal protective effect of bone marrow stem cells is obtained through animal research. Our goal is to understand the mechanism of renal protection by bone marrow stem cells and to develop strategies utilizing these stem cells for the eventual treatment of humans with kidney disease.
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Introduction
There are lineage-committed and relatively more differentiated cells as well as primitive stem cells in the bone marrow. Bone marrow stem cells are classified into hematopoietic stem cells (HSC) that give rise to all cells of the hematopoietic system and mesenchymal stem cells (MSC) that support hematopoiesis. In addition to their role in hematopoiesis, both HSC and MSC have been shown to have the ability to differentiate into many other types of cells in vivo or in culture conditions. In the last few years, reports of bone marrow cell conversion into various types of renal cells have emerged. MSC have also been shown to provide renal protection by paracrine effects. The diverse developmental potential of bone marrow stem cells as well as the easy access to HSC and expandable nature of MSC in cultures opens the possibility of stem cell-based therapy for kidney diseases. The purpose of this review article is to prove a general overview of bone marrow stem cell biology and discuss strategies in developing bone marrow stem cell-based therapy for the treatment of kidney diseases.
Hematopoietic stem cells and stem cell niche
HSC discovery and isolation
The presence of HSC was first suggested by James Till and Ernest McCulloch in a landmark study in 1961 [1]. In studying radiation sensitivity of mouse bone marrow cells, they discovered that bone marrow contained a unique population of cells that were capable of forming macroscopic cell colonies in the spleen of the transplant recipient mice. The cells were then called “spleen colony-forming units” (CFU-S) and were later found to be able to self-renew and differentiate into all types of blood cells [2]. This discovery led to the definition of the characteristics of all stem cells: self-renewal and lineage differentiation. Because of their pioneering stem cell research, Till and McCulloch received the Lasker Basic Medical Research Award in 2005 [3]. The definitive isolation of mouse HSC was in 1988 by the research team led by Irving Weissman [4]. After immunodepletion of lineage-differentiated cells and staining lineage undifferentiated cells (Lin- cells) with cell-surface markers Sca-1 and c-kit, Lin-Sca-1+c-kit+ cells were isolated by fluorescence-activated cell sorter (FACS) and shown to have stem cell properties [4, 5]. The balance between self-renewal and lineage differentiation of HSC ensures the lifetime supply of all types of blood cells. Based on their ability of self-renewal, HSC can be divided into long-term repopulating HSC (LT-HSC) that can self-renew and reconstitute the hematopoietic system for life, and short-term repopulating HSC (ST-HSC) that have limited or no self-renewal ability and can only sustain hematopoiesis for a few weeks [6]. LT-HSC are considered true stem cells and account for about 1 in 105 of bone marrow cells in mice [7, 8].
The discovery of cell-surface markers provides the advantage in isolation and further study of HSC. For example, CD34 is another commonly used cell-surface marker for isolation of human as well murine HSC, a finding that followed the discovery that a small fraction of human bone marrow cells express CD34 [9]. However, recent research indicates that CD34+ stem cells can only give short-term repopulation of the hematopoietic systems in the recipients, whereas the CD34- population is actually more primitive [6] and can self-renew to give long-term repopulation of blood cells [10]. Alternatively, HSC can be isolated using their physical properties. Based on low staining intensity with DNA dye Hoechst 33342 or mitochondrial membrane dye rhodamine 123, side population (SP) cells, or Rhlo cells with stem cell characteristics have been isolated, respectively [11, 12].
HSC development
The hematopoietic system in vertebrates is mesoderm-derived. During embryogenesis, the first blood cells in mice and men appear in the yolk sac. The primitive nucleated red cells enter the circulation when the embryonic and extraembryonic vessels link together [13]. It was originally thought that adult HSC originated in the yolk sac, migrated to the fetal liver, and subsequently colonized the adult bone marrow. More recent studies have identified the aorta–gonad–mesonephros (AGM) region and more specifically, the dorsal aorta, as the first site for adult HSC formation [14, 15]. The development of stem cells to lineage-differentiated mature cells is a continuum. HSC are a functionally heterogeneous population of cells, even when they are isolated based on their uniformed expression of surface markers. The heterogeneity is reflected by their homing efficiency, the ability to self-renew and to repopulate irradiated hosts, and differences in lineage-biased differentiation [16–18]. This heterogeneity has been documented during development and aging. For example, aged HSC produce more myeloid progeny than their younger counterparts. This lineage bias is only partially corrected by exposure to a younger environment [19, 20]. The mechanisms of stem cell heterogeneity are not fully understood at the present time. The model of a single type of “mother of all HSC” that produces diverse daughter cells under the control of a variety of extrinsic and intrinsic factors has been suggested [21–23]. Alternatively, the hypothesis of “many mothers” with various clonal diversities has been proposed, and there is increasing evidence favoring this hypothesis [17]. The heterogeneity of HSC may complicate the comparison of experimental results obtained by different research groups with different methods of cell isolation. Similarly, caution should be taken when interpreting microarray analysis data of HSC that are phenotypically homogenous but functionally heterogenous [24, 25].
Stem cell niche
The concept of a stem cell niche was first proposed by Ray Schofield in 1978 to describe a microenvironment in which HSC reside and maintain self-renewal potential. When HSC divides, one daughter cell remains in the niche as the primitive stem cell, whereas the other daughter cell leaves the niche and differentiates into more mature progeny [26]. The niche concept is supported by in vitro studies to demonstrate that bone marrow stromal cells are able of supporting hematopoiesis and maintaining HSC for long-term repopulation as a result of HSC self-renewal [27, 28]. In vivo stem cell niches were defined in Drosophila ovary and testis [29–31] and in mammalian skin and gut [32–35] before identification of HSC niche in mice in 2003. Zhang and Calvi independently reported the localization of an HSC niche to the endosteal space [36, 37]. Using genetic strategies, these investigators showed that osteoblasts were the important niche cells controlling the number of long-term repopulating HSC. LT-HSC colocalized with spindle-shaped osteoblasts lining the inner bone surface. The number of LT-HSC increased with the increasing number of osteoblasts induced by injection of parathyroid hormone (PTH) or in transgenic mice with conditional inactivation of bone morphogenetic protein (BMP) receptor type IA (BMPRIA). Furthermore, Adams et al. demonstrated that in response to high calcium concentration (as high as 40 mM) in the endosteal niche, HSC that expressed high levels of calcium-sensing receptor (CaR) migrated and engrafted to the endosteal niche [38]. Bone marrow is the preferred homing site for HSC. It is unknown whether chronically elevated levels of PTH observed in humans with renal failure has the same effect on HSC homing and mobilization as do cyclic levels of PTH created by PTH injection. However, the effects of PTH and BMP signaling on HSC provides potential targets for stem-cell-based therapy. More recently, endothelia of bone marrow sinusoidal vessels were found to be the vascular niche for HSC [39, 40].
Stem cell homing and mobilization
One of the most clinically relevant features of HSC is homing and mobilization. HSC homing involves the events of stem cell adhesion and rolling along the bone marrow sinusoidal endothelial cells, transendothelial migration, and lodgement in the bone marrow niches. HSC mobilization from bone marrow into extramedullary tissues is believed to be governed by similar mechanisms as HSC homing [41–43]. The interaction of HSC with endothelial cells requires binding of integrins, sialomucins, and CD44 molecules expressed on the HSC with E- and P-selectin and vascular adhesion molecule-1 (VCAM-1) expressed by endothelial cells. Integrin binding, particularly α4β1 integrin or very late antigen-4 (VLA-4) with the counterreceptor VCAM-1, ensures firm HSC adhesion with endothelial cells. The important role of VLA-4 and VCAM-1 in stem cell homing is demonstrated by an early study in which preexposure of blocking antibodies to VLA-4 or VCAM-1 reduced the homing of transplanted murine bone marrow cells to the host bone marrow [44]. Other key players are stromal-derived-factor-1 (SDF-1) and its receptor CXCR4 [42]. SDF-1 belongs to the chemokine family and is expressed by a wide variety of cells, including bone marrow stromal cells and endothelial cells. It consists of cell-bound, extracellular matrix-bound, and soluble forms. SDF-1 binding with CXCR4 expressed on HSC and hematopoietic progenitor cells elicits hematopoietic cell adhesion and transmigration, which is mainly mediated via Gi-protein second messenger. Cooperation and compensation between VAL-4/VCAM-1 and SDF-1/CXCR4 in mediating HSC homing has recently been shown in mice. In that study, a combined blockade of α4 integrin/VCAM-1 and SDF-1/CXCR4 dramatically reduced bone marrow cell homing [45]. Similarly, studies in humans showed that inhibition of CXCR4 by a small molecule AMD3100 reduced homing and enhanced HSC mobilization into the circulation. As a result, a larger number of HSC can be collected for autologous stem cell transplantation. The study provides a good example of clinical usefulness by modulating HSC homing and mobilization [46–48].
Discovery and therapeutic values of mesenchymal stem cells
MSC derivation
Mesenchymal stem cells are defined by two features: the ability to undergo sustained proliferation in vitro, and the potential to give rise to cells of mesenchymal lineages, including osteocytes, chondrocytes, and adipocytes [49, 50]. Most of our knowledge of MSC is obtained from cultures of the cells in vitro. Friedenstein et al. first cultured fibroblast precursor cells isolated from mouse bone marrow in 1976. The cells were adherent to a plastic surface and were able to differentiate into osteoblasts, adipocytes, and chondrocytes in vitro [51, 52]. Cells with similar phenotype were identified from cultures of human bone marrow cells [53] and more recently from many other sources, including fat, umbilical cord, scalp, placenta, and exfoliated deciduous teeth in humans and other species [54–59]. The cells are generated by a variety of methods in culture medium supplemented with bovine or human serum to obtain plastic-adherent, spindle-shaped, and fibroblast-looking cells. A large number of cells can be achieved after several passages. The culture-derived mesenchymal cells are highly heterogeneous, and some of the cells possess mesenchymal stem cell properties. There are no specific markers to distinguish mesenchymal stem cells from the rest of stromal cells, and virtually all published results are obtained from cultured cells, with different methods of isolation and expansion. At present, MSC are defined by a combination of physical, phenotypical, and functional properties.
Nomenclature and criteria to define MSC
To clarify nomenclature and promote comparison and contrast of study outcomes, the Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy (ISCT) published a position statement in 2005 suggesting that “the fibroblast-like plastic-adherent cells, regardless of the tissue from which they are isolated, be termed multipotent mesenchymal stromal cells, while the term mesenchymal stem cells is used only for cells that meet the specific stem cell criteria. The widely recognized acronym, MSC, may be used for both mesenchymal stromal cells and mesenchymal stem cells” [60]. Investigators are encouraged to define MSC in specific studies. More recently, another position statement from ISCT provided minimal criteria for defining human multipotent mesenchymal stromal cells as follows: “First, MSC must be plastic-adherent when maintained in standard culture conditions. Second, MSC must express CD105, CD73 and CD90, and lack expression of CD45, CD34, CD14 or CD11b, CD79α or CD19 and HLA-DR surface molecules. Third, MSC must differentiate to osteoblasts, adipocytes and chondroblasts in vitro” [61]. These criteria set the standard for cell-surface determinants and phenotype of human MSC.
MSC origin and function
Despite the well-characterized properties of MSC in vitro, the exact origin, physiological function, and development of MSC in vivo have remained elusive. Very recently, using the technique of genetic marking and lineage tracing in mice, Takashima et al. showed the surprising results that during early embryogenesis, the first wave of MSC is derived from neuroepithelium and neural crest rather than mesoderm. However, MSC derived from this pathway are transient and are replaced by MSC from other unidentified sources later in the development. By 4 weeks of age, neuroepithelium- and neural-crest-derived MSC constitute an insignificant portion of MSC isolated from bone tissue. The number of MSC decreases with age [62]. That study demonstrates convincingly that MSC are actually present in vivo rather than an in vitro culture product.
MSC have diverse functions. They provide extracellular matrix, cytokines, and growth factors to support the growth and differentiation of hematopoietic cells in ex vivo culture [49, 51, 52, 63–67]. Other well-demonstrated characteristics of MSC include direct differentiation into other cells of mesenchymal origin, such as osteoblasts, adipocytes, chondroblasts, and myoblasts. It has been demonstrated that MSC can differentiate into neurons and astrocytes, cardiomyocytes, and endothelial cells [68–72]. Studies conducted by Verfaillie’s group showed in vitro differentiation into many types of cells with mesoderm, neuroectoderm, and endoderm characteristics by multipotent adult progenitor cells (MAPCs) derived from mice and rats. When injected into blastocysts, single MAPC contributed to most, if not all, somatic cell types [73]. The multipotent potential of MAPCs has been found by many scientists around the world to be difficult to replicate [74]. One major difference in deriving MAPCs from most methods of generating MSC is that MAPCs were derived after plating at low density and requiring special culture conditions. Since MAPCs were generated by long-term and low-density culture in vitro, the existence of such cells in vivo has been questioned. The issue of “nature vs. nurture” in derivation of MAPCs has not been settled.
MSC therapeutic values
The ability of in vivo differentiation and their role in immunomodulation suggest that MSC may have clinical implications [75]. Animal and preclinical studies led to clinical trials in testing the safety and efficacy of MSC in treating cardiovascular diseases such as acute myocardial infarction, end-stage ischemic heart disease, and vascular restenosis [76–79]; skeletal and muscular diseases such as osteogenesis imperfecta [80, 81]; neurological diseases such as amyotrophic lateral sclerosis [82]; and lysosomal storage diseases such as Hurler syndrome and metachromatic leukodystrophy [83]. Intravenous, intracoronary, or intraspinal cord injection of MSC has proven to be safe, and some structural and/or functional improvement of the diseased organs has been observed with MSC treatment. The therapeutic values of MSC in treating hematological diseases are largely related to their paracrine effect and immunomodulation. MSC can produce cytokines to support hematopoiesis [84–86]. Cotransplantation of HSC and MSC enhances bone marrow recovery from chemotherapy or radiation therapy [87]. The immunosuppressive property of MSC has been utilized for potential treatment of graft-versus-host disease (GVHD) [87].
Hematopoietic stem cells in renal repair after acute kidney injury (AKI)
AKI pathogenesis and consequences
The main pathogenesis of AKI resulting from ischemia-reperfusion injury (IRI) includes acute tubular necrosis and apoptosis, glomerular injury, and inflammation [88, 89]. Inflammation and leukocyte infiltration occurs within hours of renal injury and is mediated by adhesion molecules, including integrins, selectins, cytokines, chemokines, and eicosanoid metabolites [90–92]. Subsets of leukocytes may exert different effects on the kidney. While neutrophils and macrophages are believed to cause injury to the kidney, the effect of lymphocyte infiltration on the kidney is controversial [91, 93, 94]. Kale et al. showed HSC mobilization into the circulation 24 h postrenal IRI, and transplantation of Lin- bone marrow cells resulted in acceleration of renal functional recovery [95]. In contrast, HSC mobilization with its associated granulocytosis led to worsening of renal structure and function in mice with renal IRI [96], suggesting that deleterious effects by infiltrating granulocytes may override the protective effects of HSC.
Renal injury results in decreased renal plasma flow and glomerular filtration rate (GFR) and triggers tubular regeneration. We and others have shown that both intrarenal cells (surviving mature tubular epithelial cells and renal stem/progenitor cells) and bone marrow stem cells (HSC and MSC) contribute to renal repair [95, 97–101]. Following acute renal injury, surviving mature epithelial cells dedifferentiate, proliferate, and redifferentiate to reestablish tubule structure and function. A population of slow-cycling cells located in the renal papilla of rats and mice has been shown to resemble some stem cell properties and may migrate to the site of injury for renal repair [102]. Quantitatively, intrarenal cells were the main source for regenerating cells [98, 103]. AKI carries high morbidity and high mortality [88, 104, 105]. At the present time, the only treatment option for AKI is supportive measures while waiting for renal function to return. The recovery from AKI is incomplete, and long-term consequences of AKI can be severe [106–108]. For example, in pediatric patients who survived AKI, 59% had chronic renal injury, and 9% developed end-stage renal disease in 3–5 years [109]. This calls for the development of new and more effective treatment for AKI. The following summarizes our understanding of the role of bone marrow stem cells in renal repair and discusses the strategies in using bone marrow stem cells as a unique cellular source for potential therapy for kidney diseases.
HSC conversion into renal cells
HSC have been shown to differentiate into many types of nonhematopoietic cells in the body or in the culture [110–112]. We and others have shown that bone marrow stem cells have the ability to localize to the injured kidney and be converted to various types of renal cells, including tubular epithelial cells, interstitial cells, endothelial cells, mesangial cells, and podocytes [95, 97, 98, 103, 113–117]. Using laser scanning confocal microscopy and 3-dimentional image reconstruction, we showed that unfractionated male-derived bone marrow cells could integrate into the proximal tubules, thick ascending limbs, distal tubules, and collecting ducts of the female postischemic kidney. An average of 1.8% tubular epithelial cells were bone-marrow-derived and were negative for the leukocyte marker CD45, indicating the absence of infiltrating white cells in the tubules 28 days postischemic injury [118]. Conversion of bone marrow cells to epithelial cells suggests that bone marrow cells are capable of responding to the signals generated from the microenvironment in the injured kidney and integrating into the tubules for renal repair. However, it remains unclear whether the conversion of bone marrow cells to renal cells is due to differentiation of primitive HSC or HSC progeny that develop in vivo.
In animal models of IRI, most renal repair occurs in the first week postinjury [119], and most regenerating cells originate from intrarenal cells [98, 103]. We showed that with a single injection of freshly isolated and unfractionated bone marrow cells, the earliest time point at which bone-marrow-derived cells could be detected in the tubules was 5 days postrenal IRI. At 7 days, only 1 or 2 tubular cells per kidney section were donor-derived. No improvement of blood urea nitrogen (BUN) was observed, indicating that this modality has not produced physiologically relevant improvement in renal function. In addition, more collagenous interstitial lesions were observed in the kidneys of mice 28 days postinjection with unfractionated bone marrow cells, suggesting that unfractionated bone marrow cells might be involved in interstitial fibrosis at a later stage. To use HSC for potential treatment of AKI, strategies need to be developed to promote early and sustained transmigration of HSC into the kidney, induce the cells to commit to a renal cells fate, and enhance HSC conversion into renal tubular cells within the first 2 weeks following injury, when most renal repair occurs. It is believed that lineage-differentiated hematopoietic cells, such as macrophages, can be involved in interstitial fibrosis following renal ischemic injury. Future studies to select specific population(s) of bone marrow cells may optimize the therapeutic potential while minimizing the adverse effect of the bone marrow hematopoietic cells.
Low frequency of fusion between bone marrow cells and renal cells
Utilization of HSC for cell therapy of AKI requires understanding the mechanisms of cell conversion. Fusion of bone marrow cells with embryonic stem (ES) cells in cultures has been reported. Fused cells changed to ES-like cells with pluripotent potential [120]. Bone marrow cells could also fuse with hepatocytes, Purkinje neurons, intestinal stem cells, cardiomyocytes, or endothelial cells [121–127]. To examine whether cell fusion occurs in the postischemic kidneys, we used the strategies of cre/loxP and sex-mismatched systems by injecting bone marrow cells isolated from male R26R-EYFP mice into female creksp mice with renal IRI. After 28 days, cell fusion was detected by chromosome fluorescent in situ hybridization (FISH) for polysomy of the sex chromosomes and by quantitative real-time polymerase chain reaction (qRT-PCR) and immunostaining for enhanced yellow fluorescent protein (EYFP). X and Y chromosome FISH detected four cells containing 3X1Y chromosomes and five cells containing 2X1Y chromosomes among 14,168 total kidney cells examined in the transplanted female mouse kidneys. Five cells with polysomy were detected from a total of 132 bone-marrow-derived tubule cells (3.8%). Cell fusion was verified by the de novo expression of EYFP in the kidney tubules. The frequency of fusion between bone marrow cells and epithelial cells was 0.066% (∼7 per 104 tubular cells) using EYFP detection method. No cell fusion was observed in the contralateral or sham-operated kidneys, suggesting that ischemic injury was required for cell fusion. The requirement of injury for cell fusion was confirmed in cell cultures in vitro. Collectively, these results indicate that bone marrow cells can fuse with renal epithelial cells after ischemic injury, but the low frequency of cell fusion does not account for the majority of the observed conversion of bone marrow cells into kidney cells [118]. In comparison, when wild-type HSC were transplanted into mice with hereditary tyrosinemia, the transplanted cells fused with hepatocytes [122, 123]. The fused cells proliferated extensively and generated millions of functional, highly aneuploid progeny. In these studies, strong selection pressure (mutation of hepatocytes and drug therapy followed by drug withdrawal) favored engraftment of wild-type HSC. In our study, the low number of fused cells in the kidney suggests low rates of proliferation. Although cell fusion may be used as a vehicle for delivering genes or pharmacological agents into target organs, such as the liver, the low frequency of cell fusion in postischemic kidneys may make this approach ineffective in stimulating renal function recovery.
Mesenchymal stem cells in renal repair
MSC differentiation to tubular epithelial cells
The role of MSC in renal protection has been studied. Morigi et al. isolated MSC from mouse bone marrow and transplanted them into the mice with cisplatin-induced acute chemical injury of the kidneys. Improvement in renal structure was observed 4 days post-MSC transplantation, and significant increase in tubular cell proliferation was detected at 4 and 11 days post-MSC treatment, suggesting stimulation of tubular cell growth by factors released by MSC. Renal structure improvement was accompanied by the acceleration of renal function recovery indicated by lower levels of BUN. Kidney analysis at 4 and 29 days post-MSC injection showed MSC differentiation into tubular epithelial cells. In contrast, HSC transplantation led to minimal HSC incorporation into tubules at 4 days post cell injection and no improvement in renal function was detected [101]. This is one of the first studies demonstrating renal protection by MSC differentiation into tubular epithelial cells and possible trophic factor secretion by MSC to enhance renal repair. It is interesting to note that the recipient mice did not have bone marrow ablation with total body irradiation or chemical treatment to prevent rejection. Better MSC engraftment compared with that seen with HSC may be partially due to MSC immune privilege status. MSC differentiation to tubular epithelial cells and the effect of MSC in promoting epithelial proliferation were also reported in mice with glycerol-induced acute renal failure [128], providing further support that MSC might be a direct cellular source for tubular regeneration. However, in both studies, no quantitative assessment of MSC contribution to tubular repair was performed.
Paracrine effect of MSC in renal protection
Togel et al. reported renal protection by MSC in rats with renal IRI. However, renal protection was mediated through proinflammatory cytokine inhibition and anti-inflammatory cytokine stimulation in postischemic kidneys rather than MSC differentiation into renal tubular epithelial cells [100]. In vivo tracking of injected MSC labeled with iron dextran demonstrated that most MSC were localized to the glomerular capillaries, and no tubules showed iron labeling 3 days post-MSC injection [129], supporting the paracrine effect of MSC in renal protection. More recently, Togel et al. showed that MSC produced vascular endothelial growth factor (VEGF), human growth factor (HGF), and insulin-like growth factor (IGF)-1 in cultures. MSC-conditioned medium inhibited apoptosis and promoted growth in cultured endothelial cells. Intra-arterial infusion of MSC into mice with renal IRI decreased apoptosis in the kidneys in the areas there MSC were attached to the microvasculature. These results suggest that paracrine effect on renal vasculature may contribute to renal protection [130] and provide a good example of how exogenous stem cells may interact with intrarenal cells to enhance the potential of endogenous cells for renal repair. At the present time, it is not clear what other factors secreted by MSC can offer renal protection. Identification and purification of these factors would provide new avenues for pharmacological therapy of AKI and avoid injection of a large volume of MSC-conditioned medium.
MSC mobilization into injured kidneys
To understand the mechanism of intrarenal migration of MSC, Herrera et al. examined kidneys injured by intramuscular injection of glycerol and found that the expression of hyaluronic acid (HA) was increased in the kidneys. MSC isolated from mice lacking CD44, the receptor for HA, were unable to localize to the injured kidneys and lacked renal protection. The defect of intrarenal migration of CD44-null MSC was corrected by transfection of the cells with cDNA encoding wild-type CD44. Their results suggest that MSC migration into the injured kidney is mediated by elevated levels of renal HA, which binds to its receptor CD44 expressed on MSC [131]. Because CD44 has multiple functions, including regulation of cell survival, proliferation, and differentiation, future studies by overexpression of CD44 may provide answers as to whether CD44 modulation on MSC would result in an increased renal transmigration and greater enhancement of renal repair.
Summary and future directions
In summary, stem cells residing in bone marrow can be harvested easily and have the potential to repair injured organs, such as the kidney (Fig. 1). Animal studies have demonstrated that both HSC and MSC can migrate into the kidney and differentiate into tubular epithelial cells. Future research to understand the mechanisms of transmigration and conversion of the cells into renal cells will help in the design of new strategies in using bone marrow stem cells as direct cellular sources for renal repair. In addition, the unique features of immunomodulation and trophic effect of MSC can be further explored to decrease inflammation and injury and promote regeneration from intrinsic renal cells (Table 1). Bone marrow stem cells have been used in clinical trials to treat a broad range of diseases, including hematological, neurological, cardiac, and genetic and metabolic diseases. We believe that bone marrow stem cell-based therapy will eventually become a reality in regenerating kidneys and will create significant impact in improving the quality of life in humans with kidney diseases.
Pathogenesis of acute kidney injury and the role of bone marrow stem cells in renal repair. Acute kidney injury is demonstrated by inflammation, detachment of tubular epithelial cells from the basement membrane, and endothelial cell injury (yellow) in renal blood vessels (BV). Renal repair following acute injury is characterized by proliferation of intrarenal cells, including surviving tubular epithelial cells and potential renal stem/progenitor cells to reline the tubular structure. Hematopoietic stem cells (HSC) and mesenchymal stem cells (MSC) can transmigrate into the kidney and integrate into the tubules for conversion to tubular epithelial cells. MSC also decrease inflammation, prevent cell death, and promote proliferation of endothelial and tubular epithelial cells via paracrine mechanisms
Reference
Till JE, McCulloch EA (1961) A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat Res 14:213–222
Siminovitch L, McCulloch EA, Till JE (1963) The Distribution of Colony-Forming Cells among Spleen Colonies. J Cell Physiol 62:327–336
McCulloch EA, Till JE (2005) Perspectives on the properties of stem cells. Nat Med 11(10):1026–1028
Spangrude GJ, Heimfeld S, Weissman IL (1988) Purification and characterization of mouse hematopoietic stem cells. Science 241(4861):58–62
Ikuta K, Weissman IL (1992) Evidence that hematopoietic stem cells express mouse c-kit but do not depend on steel factor for their generation. Proc Natl Acad Sci USA 89(4):1502–1506
Zhong JF, Zhao Y, Sutton S, Su A, Zhan Y, Zhu L, Yan C, Gallaher T, Johnston PB, Anderson WF, Cooke MP (2005) Gene expression profile of murine long-term reconstituting vs. short-term reconstituting hematopoietic stem cells. Proc Natl Acad Sci USA 102(7):2448–2453
Harrison DE, Stone M, Astle CM (1990) Effects of transplantation on the primitive immunohematopoietic stem cell. J Exp Med 172(2):431–437
Uchida N, Jerabek L, Weissman IL (1996) Searching for hematopoietic stem cells. II. The heterogeneity of Thy-1.1(lo)Lin(-/lo)Sca-1+ mouse hematopoietic stem cells separated by counterflow centrifugal elutriation. Exp Hematol 24(5):649–659
Civin CI, Strauss LC, Brovall C, Fackler MJ, Schwartz JF, Shaper JH (1984) Antigenic analysis of hematopoiesis. III. A hematopoietic progenitor cell surface antigen defined by a monoclonal antibody raised against KG-1a cells. J Immunol 133(1):157–165
Sato T, Laver JH, Ogawa M (1999) Reversible expression of CD34 by murine hematopoietic stem cells. Blood 94(8):2548–2554
Goodell MA, Brose K, Paradis G, Conner AS, Mulligan RC (1996) Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J Exp Med 183(4):1797–1806
Wolf NS, Kone A, Priestley GV, Bartelmez SH (1993) In vivo and in vitro characterization of long-term repopulating primitive hematopoietic cells isolated by sequential Hoechst 33342- rhodamine 123 FACS selection. Exp Hematol 21(5):614–622
Dzierzak E, Medvinsky A (1995) Mouse embryonic hematopoiesis. Trends Genet 11(9):359–366
Durand C, Dzierzak E (2005) Embryonic beginnings of adult hematopoietic stem cells. Haematologica 90(1):100–108
Dzierzak E (2005) The emergence of definitive hematopoietic stem cells in the mammal. Curr Opin Hematol 12(3):197–202
Sieburg HB, Cho RH, Dykstra B, Uchida N, Eaves CJ, Muller-Sieburg CE (2006) The hematopoietic stem compartment consists of a limited number of discrete stem cell subsets. Blood 107(6):2311–2316
Muller-Sieburg CE, Sieburg HB (2006) Clonal diversity of the stem cell compartment. Curr Opin Hematol 13(4):243–248
Quesenberry PJ (2006) The continuum model of marrow stem cell regulation. Curr Opin Hematol 13(4):216–221
Sudo K, Ema H, Morita Y, Nakauchi H (2000) Age-associated characteristics of murine hematopoietic stem cells. J Exp Med 192(9):1273–1280
Liang Y, Van Zant G, Szilvassy SJ (2005) Effects of aging on the homing and engraftment of murine hematopoietic stem and progenitor cells. Blood 106(4):1479–1487
Abkowitz JL, Catlin SN, Guttorp P (1996) Evidence that hematopoiesis may be a stochastic process in vivo. Nat Med 2(2):190–197
Blackett N, Gordon M (1999) "Stochastic" -40 years of use and abuse. Blood 93(9):3148–3149
Metcalf D (1998) Lineage commitment and maturation in hematopoietic cells: the case for extrinsic regulation. Blood 92(2):345–347; discussion 352
Phillips RL, Ernst RE, Brunk B, Ivanova N, Mahan MA, Deanehan JK, Moore KA, Overton GC, Lemischka IR (2000) The genetic program of hematopoietic stem cells. Science 288(5471):1635–1640
Park IK, He Y, Lin F, Laerum OD, Tian Q, Bumgarner R, Klug CA, Li K, Kuhr C, Doyle MJ, Xie T, Schummer M, Sun Y, Goldsmith A, Clarke MF, Weissman IL, Hood L, Li L (2002) Differential gene expression profiling of adult murine hematopoietic stem cells. Blood 99(2):488–498
Schofield R (1978) The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells 4(1–2):7–25
Wineman J, Moore K, Lemischka I, Muller-Sieburg C (1996) Functional heterogeneity of the hematopoietic microenvironment: rare stromal elements maintain long-term repopulating stem cells. Blood 87(10):4082–4090
Wineman JP, Nishikawa S, Muller-Sieburg CE (1993) Maintenance of high levels of pluripotent hematopoietic stem cells in vitro: effect of stromal cells and c-kit. Blood 81(2):365–372
Lin H, Spradling AC (1997) A novel group of pumilio mutations affects the asymmetric division of germline stem cells in the Drosophila ovary. Development 124(12):2463–2476
Xie T, Spradling AC (2000) A niche maintaining germ line stem cells in the Drosophila ovary. Science 290(5490):328–330
Kiger AA, Jones DL, Schulz C, Rogers MB, Fuller MT (2001) Stem cell self-renewal specified by JAK-STAT activation in response to a support cell cue. Science 294(5551):2542–2545
Alonso L, Fuchs E (2003) Stem cells of the skin epithelium. Proc Natl Acad Sci USA 100(Suppl 1):11830–11835
Kopan R, Lee J, Lin MH, Syder AJ, Kesterson J, Crutchfield N, Li CR, Wu W, Books J, Gordon JI (2002) Genetic mosaic analysis indicates that the bulb region of coat hair follicles contains a resident population of several active multipotent epithelial lineage progenitors. Dev Biol 242(1):44–57
Marshman E, Booth C, Potten CS (2002) The intestinal epithelial stem cell. Bioessays 24(1):91–98
Nishimura EK, Jordan SA, Oshima H, Yoshida H, Osawa M, Moriyama M, Jackson IJ, Barrandon Y, Miyachi Y, Nishikawa S (2002) Dominant role of the niche in melanocyte stem-cell fate determination. Nature 416(6883):854–860
Zhang J, Niu C, Ye L, Huang H, He X, Tong WG, Ross J, Haug J, Johnson T, Feng JQ, Harris S, Wiedemann LM, Mishina Y, Li L (2003) Identification of the haematopoietic stem cell niche and control of the niche size. Nature 425(6960):836–841
Calvi LM, Adams GB, Weibrecht KW, Weber JM, Olson DP, Knight MC, Martin RP, Schipani E, Divieti P, Bringhurst FR, Milner LA, Kronenberg HM, Scadden DT (2003) Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425(6960):841–846
Adams GB, Chabner KT, Alley IR, Olson DP, Szczepiorkowski ZM, Poznansky MC, Kos CH, Pollak MR, Brown EM, Scadden DT (2006) Stem cell engraftment at the endosteal niche is specified by the calcium-sensing receptor. Nature 439(7076):599–603
Kopp HG, Avecilla ST, Hooper AT, Rafii S (2005) The bone marrow vascular niche: home of HSC differentiation and mobilization. Physiology (Bethesda) 20:349–356
Kiel MJ, Yilmaz OH, Iwashita T, Terhorst C, Morrison SJ (2005) SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 121(7):1109–1121
Chute JP (2006) Stem cell homing. Curr Opin Hematol 13(6):399–406
Kucia M, Reca R, Miekus K, Wanzeck J, Wojakowski W, Janowska-Wieczorek A, Ratajczak J, Ratajczak MZ (2005) Trafficking of normal stem cells and metastasis of cancer stem cells involve similar mechanisms: pivotal role of the SDF-1-CXCR4 axis. Stem Cells 23(7):879–894
Lapidot T, Dar A, Kollet O (2005) How do stem cells find their way home? Blood 106(6):1901–1910
Papayannopoulou T, Craddock C, Nakamoto B, Priestley GV, Wolf NS (1995) The VLA4/VCAM-1 adhesion pathway defines contrasting mechanisms of lodgement of transplanted murine hemopoietic progenitors between bone marrow and spleen. Proc Natl Acad Sci USA 92(21):9647–9651
Bonig H, Priestley GV, Papayannopoulou T (2006) Hierarchy of molecular-pathway usage in bone marrow homing and its shift by cytokines. Blood 107(1):79–86
Grignani G, Perissinotto E, Cavalloni G, Carnevale Schianca F, Aglietta M (2005) Clinical use of AMD3100 to mobilize CD34+ cells in patients affected by non-Hodgkin’s lymphoma or multiple myeloma. J Clin Oncol 23(16):3871–3872; author reply 3872–3873
Devine SM, Flomenberg N, Vesole DH, Liesveld J, Weisdorf D, Badel K, Calandra G, DiPersio JF (2004) Rapid mobilization of CD34+ cells following administration of the CXCR4 antagonist AMD3100 to patients with multiple myeloma and non-Hodgkin’s lymphoma. J Clin Oncol 22(6):1095–1102
Fricker SP, Anastassov V, Cox J, Darkes MC, Grujic O, Idzan SR, Labrecque J, Lau G, Mosi RM, Nelson KL, Qin L, Santucci Z, Wong RS (2006) Characterization of the molecular pharmacology of AMD3100: a specific antagonist of the G-protein coupled chemokine receptor, CXCR4. Biochem Pharmacol 72(5):588–596
Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284(5411):143–147
Prockop DJ (1997) Marrow stromal cells as stem cells for nonhematopoietic tissues. Science 276(5309):71–74
Friedenstein AJ, Chailakhyan RK, Latsinik NV, Panasyuk AF, Keiliss-Borok IV (1974) Stromal cells responsible for transferring the microenvironment of the hemopoietic tissues. Cloning in vitro and retransplantation in vivo. Transplantation 17(4):331–340
Friedenstein AJ, Gorskaja JF, Kulagina NN (1976) Fibroblast precursors in normal and irradiated mouse hematopoietic organs. Exp Hematol 4(5):267–274
Keating A, Singer JW, Killen PD, Striker GE, Salo AC, Sanders J, Thomas ED, Thorning D, Fialkow PJ (1982) Donor origin of the in vitro haematopoietic microenvironment after marrow transplantation in man. Nature 298(5871):280–283
Zuk PA, Zhu M, Ashjian P, De Ugarte DA, Huang JI, Mizuno H, Alfonso ZC, Fraser JK, Benhaim P, Hedrick MH (2002) Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell 13(12):4279–4295
Sarugaser R, Lickorish D, Baksh D, Hosseini MM, Davies JE (2005) Human umbilical cord perivascular (HUCPV) cells: a source of mesenchymal progenitors. Stem Cells 23(2):220–229
Shih DT, Lee DC, Chen SC, Tsai RY, Huang CT, Tsai CC, Shen EY, Chiu WT (2005) Isolation and characterization of neurogenic mesenchymal stem cells in human scalp tissue. Stem Cells 23(7):1012–1020
In ’t Anker PS, Scherjon SA, Kleijburg-van der Keur C, de Groot-Swings GM, Claas FH, Fibbe WE, Kanhai HH (2004) Isolation of mesenchymal stem cells of fetal or maternal origin from human placenta. Stem Cells 22(7):1338–1345
in ’t Anker PS, Noort WA, Scherjon SA, Kleijburg-van der Keur C, Kruisselbrink AB, van Bezooijen RL, Beekhuizen W, Willemze R, Kanhai HH, Fibbe WE (2003) Mesenchymal stem cells in human second-trimester bone marrow, liver, lung, and spleen exhibit a similar immunophenotype but a heterogeneous multilineage differentiation potential. Haematologica 88(8):845–852
Miura M, Gronthos S, Zhao M, Lu B, Fisher LW, Robey PG, Shi S (2003) SHED: stem cells from human exfoliated deciduous teeth. Proc Natl Acad Sci USA 100(10):5807–5812
Horwitz EM, Le Blanc K, Dominici M, Mueller I, Slaper-Cortenbach I, Marini FC, Deans RJ, Krause DS, Keating A (2005) Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement. Cytotherapy 7(5):393–395
Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop D, Horwitz E (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8(4):315–317
Takashima Y, Era T, Nakao K, Kondo S, Kasuga M, Smith AG, Nishikawa S (2007) Neuroepithelial cells supply an initial transient wave of MSC differentiation. Cell 129(7):1377–1388
Dexter TM, Simmons P, Purnell RA, Spooncer E, Schofield R (1984) The regulation of hemopoietic cell development by the stromal cell environment and diffusible regulatory molecules. Prog Clin Biol Res 148:13–33
Pereira RF, Halford KW, O’Hara MD, Leeper DB, Sokolov BP, Pollard MD, Bagasra O, Prockop DJ (1995) Cultured adherent cells from marrow can serve as long-lasting precursor cells for bone, cartilage, and lung in irradiated mice. Proc Natl Acad Sci USA 92(11):4857–4861
Sekiya I, Larson BL, Smith JR, Pochampally R, Cui JG, Prockop DJ (2002) Expansion of human adult stem cells from bone marrow stroma: conditions that maximize the yields of early progenitors and evaluate their quality. Stem Cells 20(6):530–541
Sekiya I, Vuoristo JT, Larson BL, Prockop DJ (2002) In vitro cartilage formation by human adult stem cells from bone marrow stroma defines the sequence of cellular and molecular events during chondrogenesis. Proc Natl Acad Sci USA 99(7):4397–4402
Gregory CA, Singh H, Perry AS, Prockop DJ (2003) The Wnt signaling inhibitor dickkopf-1 is required for reentry into the cell cycle of human adult stem cells from bone marrow. J Biol Chem 278(30):28067–28078
Beyer Nardi N, da Silva Meirelles L (2006) Mesenchymal stem cells: isolation, in vitro expansion and characterization. Handb Exp Pharmacol (174):249–282
Bianco P, Gehron Robey P (2000) Marrow stromal stem cells. J Clin Invest 105(12):1663–1668
Jori FP, Napolitano MA, Melone MA, Cipollaro M, Cascino A, Altucci L, Peluso G, Giordano A, Galderisi U (2005) Molecular pathways involved in neural in vitro differentiation of marrow stromal stem cells. J Cell Biochem 94(4):645–655
Makino S, Fukuda K, Miyoshi S, Konishi F, Kodama H, Pan J, Sano M, Takahashi T, Hori S, Abe H, Hata J, Umezawa A, Ogawa S (1999) Cardiomyocytes can be generated from marrow stromal cells in vitro. J Clin Invest 103(5):697–705
Reyes M, Dudek A, Jahagirdar B, Koodie L, Marker PH, Verfaillie CM (2002) Origin of endothelial progenitors in human postnatal bone marrow. J Clin Invest 109(3):337–346
Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR, Reyes M, Lenvik T, Lund T, Blackstad M, Du J, Aldrich S, Lisberg A, Low WC, Largaespada DA, Verfaillie CM (2002) Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 418(6893):41–49
Check E (2007) Stem cells: the hard copy. Nature 446(7135):485–486
Giordano A, Galderisi U, Marino IR (2007) From the laboratory bench to the patient’s bedside: an update on clinical trials with mesenchymal stem cells. J Cell Physiol 211(1):27–35
Chen SL, Fang WW, Ye F, Liu YH, Qian J, Shan SJ, Zhang JJ, Chunhua RZ, Liao LM, Lin S, Sun JP (2004) Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction. Am J Cardiol 94(1):92–95
Perin EC, Dohmann HF, Borojevic R, Silva SA, Sousa AL, Mesquita CT, Rossi MI, Carvalho AC, Dutra HS, Dohmann HJ, Silva GV, Belem L, Vivacqua R, Rangel FO, Esporcatte R, Geng YJ, Vaughn WK, Assad JA, Mesquita ET, Willerson JT (2003) Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure. Circulation 107(18):2294–2302
Strauer BE, Brehm M, Zeus T, Kostering M, Hernandez A, Sorg RV, Kogler G, Wernet P (2002) Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation 106(15):1913–1918
Wollert KC, Meyer GP, Lotz J, Ringes-Lichtenberg S, Lippolt P, Breidenbach C, Fichtner S, Korte T, Hornig B, Messinger D, Arseniev L, Hertenstein B, Ganser A, Drexler H (2004) Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet 364(9429):141–148
Horwitz EM, Prockop DJ, Fitzpatrick LA, Koo WW, Gordon PL, Neel M, Sussman M, Orchard P, Marx JC, Pyeritz RE, Brenner MK (1999) Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Nat Med 5(3):309–313
Horwitz EM, Prockop DJ, Gordon PL, Koo WW, Fitzpatrick LA, Neel MD, McCarville ME, Orchard PJ, Pyeritz RE, Brenner MK (2001) Clinical responses to bone marrow transplantation in children with severe osteogenesis imperfecta. Blood 97(5):1227–1231
Mazzini L, Fagioli F, Boccaletti R, Mareschi K, Oliveri G, Olivieri C, Pastore I, Marasso R, Madon E (2003) Stem cell therapy in amyotrophic lateral sclerosis: a methodological approach in humans. Amyotroph Lateral Scler Other Motor Neuron Disord 4(3):158–161
Koc ON, Day J, Nieder M, Gerson SL, Lazarus HM, Krivit W (2002) Allogeneic mesenchymal stem cell infusion for treatment of metachromatic leukodystrophy (MLD) and Hurler syndrome (MPS-IH). Bone Marrow Transplant 30(4):215–222
Aggarwal S, Pittenger MF (2005) Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 105(4):1815–1822
Koc ON, Lazarus HM (2001) Mesenchymal stem cells: heading into the clinic. Bone Marrow Transplant 27(3):235–239
Le Blanc K, Pittenger M (2005) Mesenchymal stem cells: progress toward promise. Cytotherapy 7(1):36–45
Lazarus HM, Koc ON, Devine SM, Curtin P, Maziarz RT, Holland HK, Shpall EJ, McCarthy P, Atkinson K, Cooper BW, Gerson SL, Laughlin MJ, Loberiza FR Jr, Moseley AB, Bacigalupo A (2005) Cotransplantation of HLA-identical sibling culture-expanded mesenchymal stem cells and hematopoietic stem cells in hematologic malignancy patients. Biol Blood Marrow Transplant 11(5):389–398
Schrier RW, Wang W, Poole B, Mitra A (2004) Acute renal failure: definitions, diagnosis, pathogenesis, and therapy. J Clin Invest 114(1):5–14
Bonventre JV (1993) Mechanisms of ischemic acute renal failure. Kidney Int 43(5):1160–1178
Bonventre JV, Zuk A (2004) Ischemic acute renal failure: an inflammatory disease? Kidney Int 66(2):480–485
Friedewald JJ, Rabb H (2004) Inflammatory cells in ischemic acute renal failure. Kidney Int 66(2):486–491
Okusa MD (2002) The inflammatory cascade in acute ischemic renal failure. Nephron 90(2):133–138
Caldwell CC, Okaya T, Martignoni A, Husted T, Schuster R, Lentsch AB (2005) Divergent functions of CD4+ T lymphocytes in acute liver inflammation and injury after ischemia-reperfusion. Am J Physiol Gastrointest Liver Physiol 289(5):G969–976
Park P, Haas M, Cunningham PN, Bao L, Alexander JJ, Quigg RJ (2002) Injury in renal ischemia-reperfusion is independent from immunoglobulins and T lymphocytes. Am J Physiol Renal Physiol 282(2):F352–357
Kale S, Karihaloo A, Clark PR, Kashgarian M, Krause DS, Cantley LG (2003) Bone marrow stem cells contribute to repair of the ischemically injured renal tubule. J Clin Invest 112(1):42–49
Togel F, Isaac J, Westenfelder C (2004) Hematopoietic stem cell mobilization-associated granulocytosis severely worsens acute renal failure. J Am Soc Nephrol 15(5):1261–1267
Lin F, Cordes K, Li L, Hood L, Couser WG, Shankland SJ, Igarashi P (2003) Hematopoietic stem cells contribute to the regeneration of renal tubules after renal ischemia-reperfusion injury in mice. J Am Soc Nephrol 14(5):1188–1199
Lin F, Moran A, Igarashi P (2005) Intrarenal cells, not bone marrow-derived cells, are the major source for regeneration in postischemic kidney. J Clin Invest 115(7):1756–1764
Duffield JS, Bonventre JV (2005) Kidney tubular epithelium is restored without replacement with bone marrow-derived cells during repair after ischemic injury. Kidney Int 68(5):1956–1961
Togel F, Hu Z, Weiss K, Isaac J, Lange C, Westenfelder C (2005) Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms. Am J Physiol Renal Physiol 289(1):F31–42
Morigi M, Imberti B, Zoja C, Corna D, Tomasoni S, Abbate M, Rottoli D, Angioletti S, Benigni A, Perico N, Alison M, Remuzzi G (2004) Mesenchymal stem cells are renotropic, helping to repair the kidney and improve function in acute renal failure. J Am Soc Nephrol 15(7):1794–1804
Oliver JA, Maarouf O, Cheema FH, Martens TP, Al-Awqati Q (2004) The renal papilla is a niche for adult kidney stem cells. J Clin Invest 114(6):795–804
Duffield JS, Park KM, Hsiao LL, Kelley VR, Scadden DT, Ichimura T, Bonventre JV (2005) Restoration of tubular epithelial cells during repair of the postischemic kidney occurs independently of bone marrow-derived stem cells. J Clin Invest 115(7):1743–1755
Loef BG, Epema AH, Smilde TD, Henning RH, Ebels T, Navis G, Stegeman CA (2005) Immediate postoperative renal function deterioration in cardiac surgical patients predicts in-hospital mortality and long-term survival. J Am Soc Nephrol 16(1):195–200
Liano F, Pascual J (1998) Outcomes in acute renal failure. Semin Nephrol 18(5):541–550
O’Donnell MP, Burne M, Daniels F, Rabb H (2002) Utility and limitations of serum creatinine as a measure of renal function in experimental renal ischemia-reperfusion injury. Transplantation 73(11):1841–1844
Basile DP, Donohoe D, Roethe K, Osborn JL (2001) Renal ischemic injury results in permanent damage to peritubular capillaries and influences long-term function. Am J Physiol Renal Physiol 281(5):F887–899
Spurgeon-Pechman KR, Donohoe DL, Mattson DL, Lund H, James L, Basile DP (2007) Recovery from acute renal failure predisposes hypertension and secondary renal disease in response to elevated sodium. Am J Physiol Renal Physiol 293(1):F269–278
Askenazi DJ, Feig DI, Graham NM, Hui-Stickle S, Goldstein SL (2006) 3–5 year longitudinal follow-up of pediatric patients after acute renal failure. Kidney Int 69(1):184–189
Ianus A, Holz GG, Theise ND, Hussain MA (2003) In vivo derivation of glucose-competent pancreatic endocrine cells from bone marrow without evidence of cell fusion. J Clin Invest 111(6):843–850
Jang YY, Collector MI, Baylin SB, Diehl AM, Sharkis SJ (2004) Hematopoietic stem cells convert into liver cells within days without fusion. Nat Cell Biol 6(6):532–539
Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM, Li B, Pickel J, McKay R, Nadal-Ginard B, Bodine DM, Leri A, Anversa P (2001) Bone marrow cells regenerate infarcted myocardium. Nature 410(6829):701–705
Poulsom R, Forbes SJ, Hodivala-Dilke K, Ryan E, Wyles S, Navaratnarasah S, Jeffery R, Hunt T, Alison M, Cook T, Pusey C, Wright NA (2001) Bone marrow contributes to renal parenchymal turnover and regeneration. J Pathol 195(2):229–235
Ito T, Suzuki A, Imai E, Okabe M, Hori M (2001) Bone marrow is a reservoir of repopulating mesangial cells during glomerular remodeling. J Am Soc Nephrol 12(12):2625–2635
Gupta S, Verfaillie C, Chmielewski D, Kim Y, Rosenberg ME (2002) A role for extrarenal cells in the regeneration following acute renal failure. Kidney Int 62(4):1285–1290
Fang TC, Alison MR, Cook HT, Jeffery R, Wright NA, Poulsom R (2005) Proliferation of bone marrow-derived cells contributes to regeneration after folic acid-induced acute tubular injury. J Am Soc Nephrol 16(6):1723–1732
Sugimoto H, Mundel TM, Sund M, Xie L, Cosgrove D, Kalluri R (2006) Bone-marrow-derived stem cells repair basement membrane collagen defects and reverse genetic kidney disease. Proc Natl Acad Sci USA 103(19):7321–7326
Li L, Truong P, Igarashi P, Lin F (2007) Injury-induced cell fusion between bone marrow-derived cells and renal cells in post-ischemic mouse kidneys. J Am Soc Nephrol (in press)
Ysebaert DK, De Greef KE, Vercauteren SR, Ghielli M, Verpooten GA, Eyskens EJ, De Broe ME (2000) Identification and kinetics of leukocytes after severe ischaemia/reperfusion renal injury. Nephrol Dial Transplant 15(10):1562–1574
Terada N, Hamazaki T, Oka M, Hoki M, Mastalerz DM, Nakano Y, Meyer EM, Morel L, Petersen BE, Scott EW (2002) Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature 416(6880):542–545
Wang X, Willenbring H, Akkari Y, Torimaru Y, Foster M, Al-Dhalimy M, Lagasse E, Finegold M, Olson S, Grompe M (2003) Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature 422(6934):897–901
Vassilopoulos G, Wang PR, Russell DW (2003) Transplanted bone marrow regenerates liver by cell fusion. Nature 422(6934):901–904
Alvarez-Dolado M, Pardal R, Garcia-Verdugo JM, Fike JR, Lee HO, Pfeffer K, Lois C, Morrison SJ, Alvarez-Buylla A (2003) Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature 425(6961):968–973
Rizvi AZ, Swain JR, Davies PS, Bailey AS, Decker AD, Willenbring H, Grompe M, Fleming WH, Wong MH (2006) Bone marrow-derived cells fuse with normal and transformed intestinal stem cells. Proc Natl Acad Sci USA 103(16):6321–6325
Oh H, Bradfute SB, Gallardo TD, Nakamura T, Gaussin V, Mishina Y, Pocius J, Michael LH, Behringer RR, Garry DJ, Entman ML, Schneider MD (2003) Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction. Proc Natl Acad Sci USA 100(21):12313–12318
Weimann JM, Johansson CB, Trejo A, Blau HM (2003) Stable reprogrammed heterokaryons form spontaneously in Purkinje neurons after bone marrow transplant. Nat Cell Biol 5(11):959–966
Peters BA, Diaz LA, Polyak K, Meszler L, Romans K, Guinan EC, Antin JH, Myerson D, Hamilton SR, Vogelstein B, Kinzler KW, Lengauer C (2005) Contribution of bone marrow-derived endothelial cells to human tumor vasculature. Nat Med 11(3):261–262
Herrera MB, Bussolati B, Bruno S, Fonsato V, Romanazzi GM, Camussi G (2004) Mesenchymal stem cells contribute to the renal repair of acute tubular epithelial injury. Int J Mol Med 14(6):1035–1041
Lange C, Togel F, Ittrich H, Clayton F, Nolte-Ernsting C, Zander AR, Westenfelder C (2005) Administered mesenchymal stem cells enhance recovery from ischemia/reperfusion-induced acute renal failure in rats. Kidney Int 68(4):1613–1617
Togel F, Weiss K, Yang Y, Hu Z, Zhang P, Westenfelder C (2007) Vasculotropic, paracrine actions of infused mesenchymal stem cells are important to the recovery from acute kidney injury. Am J Physiol Renal Physiol 292(5):F1626–1635
Herrera MB, Bussolati B, Bruno S, Morando L, Mauriello-Romanazzi G, Sanavio F, Stamenkovic I, Biancone L, Camussi G (2007) Exogenous mesenchymal stem cells localize to the kidney by means of CD44 following acute tubular injury. Kidney Int 72(4):430–441
Acknowledgments
This work was supported by National Institutes of Health (NIH) grants K08 DK062839 and R01 DK66535, and American Society of Nephrology Gottschalk Award. FL is the first recipient of the Norman Siegel Pediatric Research Grant Award. I thank Drs. Peter Igarashi and Michel Baum for helpful discussion and Laurel Johnson for secretarial support.
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Lin, F. Renal repair: role of bone marrow stem cells. Pediatr Nephrol 23, 851–861 (2008). https://doi.org/10.1007/s00467-007-0634-8
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DOI: https://doi.org/10.1007/s00467-007-0634-8