1 Introduction

Mesenchymal stem cells (MSCs) are heterogeneous sub-populations of multipotent cells and their culture characteristics, mode of actions of MSCs have been increasingly recognized over a period of more than 50 years (Dominici et al. 2006; Friedenstein et al. 1966; Trivedi et al. 2019). The International Society for Cellular Therapy (ISCT) has characterized MSCs as multipotent mesenchymal stromal cells and recommends this to refer the plastic-adherent elements from stromal tissues, while holding the term mesenchymal stem cells to refer the subpopulation that really has the two cardinal stem cell properties, i.e. self-renewal and the ability to separate down into various lineages (Dominici et al. 2006). The criteria set down by ISCT incorporate the MSCs (i) being plastic adherent, (ii) having osteogenic, adipogenic, and chondrogenic trilineage differentiation potential, (iii) and being positive (>95%) for CD 73, CD 90 and CD 105, and negative (<2%) for CD34, CD45, CD14 or CD11b (present on monocytes and macrophages), CD79-α or CD19, and HLA-DR except if stimulated with IFN-γ (Chan et al. 2006; Chan et al. 2008). They were initially identified as the supportive cells for hematopoietic stem cells (HSC), that form the microenvironmental niche, but with time, their role independent of nurture cells has emerged.

Apart from being first identified and isolated from bone marrow, MSCs have been also isolated from other sources like adipose tissue, umbilical cord, placenta and fetal membrane, dental pulp, skeletal muscle, amniotic fluid, fetal blood, peripheral blood, Wharton’s Jelly and corneal limbus and have been shown to have similar characteristics (Ab Kadir et al. 2012; Campagnoli et al. 2001; Erices et al. 2000; Gronthos et al. 2000; In’t Anker et al. 2003; Polisetty et al. 2008; Raynaud et al. 2012; Wang et al. 2004; Zuk et al. 2001). In addition to mesodermal lineage, MSCs have also exhibited transdifferentiation potential into neuroectodermal lineages like neuronal cells and endodermal lineages like hepatocytes and pancreocytes (An et al. 2014; Anghileri et al. 2008; Datta et al. 2011; Gabr et al. 2013; Govindasamy et al. 2011; Hang et al. 2014; Lee et al. 2004; Naghdi et al. 2009; Pavlova et al. 2012; Safford et al. 2002; Stock et al. 2014; Tang et al. 2012). Having regenerative potential and affinity to home to the damaged sites, MSCs have paved way in research and clinical applications in tissue regeneration, bone disorders, metabolic diseases, etc. (Horwitz et al. 2002; Koç et al. 2002; Undale et al. 2009) Other than MSC characteristics like self-renewal, multipotency and regeneration, another characteristic that has drawn the attention of clinicians and researchers is the immunoregulatory aspect of MSCs. Over the years, these added characteristics and potential have drawn the attention of clinicians and researchers. Low or absence of HLA class I antigens, protect these cells from cell-mediated cytotoxicity, thus eliminating the risk of being considered as non-self and being targeted. MSCs have been reported to secrete a multitude of growth factors and cytokines (prostaglandin, interleukins, tumor necrosis factor-stimulated gene, etc.) which contribute to the paracrine effects on the target tissue (Monsel et al. 2014). Specifically, the microvesicles released from MSCs, carrying mRNA, microRNA, and proteins induce remodeling and a stem cell-like phenotype in injured cells (Biancone et al. 2012; Chen et al. 2015). Interestingly, recent studies indicate that it’s not just MSCs, even the apoptotic, metabolically inactivated or even fragmented MSCs possess immunomodulatory potential (Gonçalves et al. 2017; Luk et al. 2016). In view of these two unique characteristics of MSCs, and the diminishing evidence for its properties of transdifferentiation, researchers and scientists have explored their potential to serve as “adjuncts” along with other forms of cell therapy. Among the different sources of MSCs, BM-derived MSCs have been studied extensively and offer the widest avenues for therapeutics in human regenerative medicine.

This review summarizes the immunoregulatory/immunomodulatory properties of BM-MSCs and their potential role as well as their proven role as a cell-based therapy.

2 Bone marrow mesenchymal stem cells

MSCs were first identified in the BM (0.01% to 0.001%) as adherent cells with the characteristic features like self-renewal and multipotency i.e. differentiating into mesodermal lineages like adipocyte, chondrocyte and osteocytes (Friedenstein et al. 1970; Koppula et al. 2010; Peister et al. 2004; Polisetti et al. 2010). Besides mesodermal lineage, BM-MSCs have also been shown to transdifferentiate into neuro-ectodermal lineages-neuronal cells and endodermal lineages hepatocytes (Lee et al. 2004; Naghdi et al. 2009; Stock et al. 2014; Tang et al. 2012). The summary of the characteristic features of BM-MSCs is enlisted in table 1. In view of their ability to home to the damaged sites and regenerate the target tissues, MSCs have paved the way for research and clinical applications in tissue regeneration, bone disorders, metabolic, etc. (Ren et al. 2008). BM-MSCs exhibit moderate levels of class I major histocompatibility complex (MHC), lack expression of class II MHC and other co-stimulatory molecules like CD 80, CD40, CD40L, Fas ligand, B7–1 or B7–2 on their surface (Deans and Moseley 2000; Hass et al. 2011; Pittenger et al. 1999; Tse et al. 2003). Fu et.al reported that BM-MSCs demonstrate upregulation of MHC-II expression upon stimulation with a minimal dose of IFN-γ (pro-inflammatory cytokine), although the expression levels of co-stimulatory molecules remained intact (Fu et al. 2015). BM-MSCs exert their effect by interacting with immune cells like B cells, T cells, NK cells and dendritic cells and also by secretion of soluble factors like growth factors and cytokines such as granulocyte-macrophage CSF (GM-CSF), macrophage-colony stimulating factor (M-CSF), Interleukin (IL) IL-6, IL-11, IL-7, IL-8, stem cell factor, thyroid peroxidase, FLT3L, stem cell-derived factor (SDF-1), hepatocyte growth factor (HGF), monocyte chemoattractant protein 1 (MCP-1), insulin growth factor 1 (IGF-1), transforming growth factor (TGF)-β, platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), angiopoietin-1 and basic fibroblast growth factor (bFGF) involved in hematopoiesis, immunomodulation, vascular stabilization (Carmeliet and Jain 2011; Majumdar et al. 2000; Park et al. 2009). This peculiar profile of BM-MSCs (summary listed in table 1), makes them immune elusive and hence a potential candidate for cellular therapies.

Table 1 Summary of Characteristics of BM-MSCs
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3 Immunomodulation by BM-MSCs

The immunoregulatory properties of BM-MSCs are facilitated by their interactions with immune cells like T cells, B cells, dendritic cells, macrophages and natural killer (NK) cells in a context and microenvironment dependent manner (Wang et al. 2014). These cells are also known to inhibit NK cell activity, B cell proliferation, DC differentiation and function (Augello et al. 2005; Jiang and Xu 2020; Sotiropoulou et al. 2006). Interestingly MSCs are also known to act as antigen-presenting cells (APC) at low concentration of IFN-γ but the response reduces at high concentration of IFN-γ (Chan et al. 2006). BM-MSCs are known to immunosuppress the local environment by virtue of their secretions (cytokines and growth factors) and cell-cell contact. For example, soluble factors like growth factors and cytokines namely prostaglandin E2 (PGE2), indoleamine 2,3-dioxygenase (IDO), IL-6 and M-CSF have been explored and evaluated in various clinical studies and the cell-based properties have been explored in many T-cell-mediated diseases like graft-versus-host disease (GVHD), Crohn’s disease, etc., via T-cell suppression (Bartholomew et al. 2002; Dean and Bishop 2003; Di Nicola et al. 2002; Duijvestein et al. 2010; Le Blanc et al. 2004). Evidence from mixed lymphocyte reactions (MLR) suggests that both undifferentiated and differentiated BM-MSCs have suppressive effects on mitogen-stimulated and alloantigen lymphocyte proliferation followed by a concomitant reduction in the production of proinflammatory cytokines such as tumor necrosis factor (TNF-α) and interferon-γ (IFN-γ) (Klyushnenkova et al. 2005; Koppula et al. 2009). Thus, the clinical applications of human BM-MSCs are substantially greater than other human Stem Cells (SC), ranging from transplantation, immune-related disorders including autoimmune disorders and cell replacement for degenerative diseases–common application for stem cells (Le Blanc et al. 2008).

4 Mechanisms of immunomodulation

Although the exact mechanism behind the immunomodulation is still evolving, MSCs have shown to exert their immunomodulatory effects by mainly two mechanisms: (1) by soluble factors and (2) by cell-cell contact (figure 1).

Figure 1
figure 1

Immunomodulatory effects of MSCs on immune cells: The immunosuppressive effects of BM-MSCs are mediated by soluble factors and cell–cell contact and exosomes. Immunomodulatory effects of BM-MSCs include suppression of B- and T-cell proliferation, induction and regulation of regulatory T cells, inhibition of NK cell function and inhibiting dendritic cell maturation and activation.

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Inflammation is a primary response by the immune system during tissue damage. Several factors and cytokines that are produced in inflamed tissue stimulate migration, proliferation, and differentiation of cells. Possibly, BM-MSCs protect cells from excessive damage by controlling the transition from inflammation to repair steps thereby preventing the production of extracellular matrix responsible for fibrosis. It has been reported that BM-MSCs can regulate the functional activity of lymphocyte and other immune cell types in a microenvironment dependent manner (Bartholomew et al. 2002; Rubtsov et al. 2012). Soluble factors such as IFN-γ and TNF-α secreted by activated lymphocytes in vitro initiate the BM-MSC mediated immunosuppression, inducing synthesis of protein factors inducible nitric oxide synthase (iNOS) and Indoleamine 2,3-dioxygenase (IDO) products (kynurenine and NO) of which have been reported to hinder lymphocyte function and proliferation (Rasmusson 2006; Raynaud et al. 2012; Ringdén et al. 2006).

Other than soluble factors, the exosomes or the extracellular vesicles from BM-MSCs, have been reported to retain immunomodulatory properties and regenerative effects suggesting for use as cell-free therapy (Lai et al. 2015; Phinney and Pittenger 2017). Due to their small size, BM-MSCs derived exosomes pass through most physiological barriers. In one of the studies, BM-MSCs derived exosomes inhibited the IFN-γ production and significantly increased production of PGE2, TGF-β, IL10 and IL-6 of PBMNCs isolated from type I diabetic mellitus (T1DM) patients (Favaro et al. 2016). Similar anti-inflammatory activity was reported in a recent study where BM-MSCs derived exosomes improved survival and ameliorated the pathologic damage of chronic graft versus host disease (cGVHD) by suppressing Th17 cells and inducing Treg (Lai et al. 2018). In some of the animal studies, BM-MSC derived exosomes attenuated the complement activation, injury-induced inflammatory response and allogenic rejection of skin grafts.BM-MSC derived exosomes also have been found to polarize activated CD4+ T cells to Tregs through inducing an M2-like anti-inflammatory phenotype in monocytes (Du et al. 2018; Zhang et al. 2014).

Although paracrine mechanisms play a substantial part in immunosuppression, they exert greater suppressive potential while in direct contact with target cells (Krampera et al. 2003). Elucidation of cell contact-dependent mechanism for immunosuppression is further complicated in comparison to the paracrine mode of action due to the presence of co-stimulation and cell adhesion molecules on both BM-MSCs and surfaces of stimulated immune cells (Newman et al. 2009). The list of candidate molecules involved in contact-dependent mechanisms of immunosuppression was narrowed down to programmed death-1 receptor/programmed death-1 receptor ligand (PD-1/PD.L1), the B7 family immune-regulatory orphan ligand H4 (B7-H4), vascular cell adhesion molecule (VCAM) and intercellular adhesion molecules of adhesion molecule family (ICAM)(Augello et al. 2005; Ren et al. 2010; Xue et al. 2010).

5 BM-MSCs and immune cells: crosstalk

Bone marrow serves as a repository of hematopoietic stem cells (HSCs) which self-renew, differentiate into cells of hematopoietic lineage, and cater sustainable production of blood. The concept of a niche was first projected in 1978 as a hub populated by stem cells and an environment conducible enough for stem cells to retain their stemness (Schofield 1978). In the 1980s, pioneering work of Friedenstein and colleagues revealed connective tissue-forming cells in bone marrow having fibroblast-like appearance and nomenclature as colony-forming units fibroblasts (CFU-f). Further transplantation experiments revealed that the transplanted colonies provided adequate microenvironment for HSC homing and subsequent hematopoiesis, emphasizing on the hypotheses of hematopoietic inductive microenvironment and HSC niche. The multipotency and the trilineage potential was demonstrated by several researchers (Beresford 1989; Owen et al. 1987; Pittenger et al. 1999). Later in 1991, Caplan coined the term mesenchymal stem cells for these stromal cells. Over last half a century, several studies have reported tangible evidence unraveling the presence and essence of precursor marrow stromal cells/nurturing cells in the hematopoietic niche supporting hematopoiesis and required for maintenance and differentiation of HSCs (Amsel and Dell 1971; Dazzi et al. 2006; Dexter et al. 1977; Johnson and Dorshkind 1986; Knospe et al. 1972; Muguruma et al. 2006; Saleh et al. 2015; Tavassoli and Crosby 1968; Wagner et al. 2007). A further study reported by Mendez et.al revealed the heterogeneous and unique bone marrow niche consisting of Hematopoietic Stem Cells (HSCs) and Mesenchymal Stem Cells (MSCs) (Méndez-Ferrer et al. 2010). While MSCs are bona fide cells catering to various processes like immunomodulation/immunosuppression and homing to damaged sites for repair/regeneration nevertheless HSCs work towards the formation of blood cells and all the immune cells. These immune cells play a major role in defense against any infections or inflammatory conditions, thereby producing immune response in the body and they do so by their ability to distinguish between self and non-self thus protecting the body. During any inflammation or tissue damage, immune response is relayed through cell–cell contact with different immune cells and secretion of soluble immune factors inducing MSC-regulated immunosuppression in a cell-dependent manner.

5.1 BM-MSCs and T cells

T Cells are the central component of the cell-mediated/adaptive immune system. Upon activation they form three different populations- helper, cytotoxic and regulatory T cells functioning in different ways These cells play a crucial role in auto-immune diseases, keeping infections and malignancies at bay. BM-MSCs are known to modulate T cells at different stages. For instance, BM-MSCs have been shown to immunoregulate T cells by inhibiting the activation and proliferation of effector T cells (both CD4+ and CD8+) via cell-cell contact and the secretion of various soluble factors (Duffy et al. 2011b; Hwu et al. 2000; Klyushnenkova et al. 2005). Upregulation of soluble factors like PGE2, TGF-β1 and HGF have been implicated in inhibiting T cell proliferation by IFN-γ primed BM-MSCs (Liang et al. 2018). Another possible mechanism of T cell suppression by BM-MSCs might be via IDO induced by IFN-γ. IDO induces tryptophan depletion leading to T cell suppression (Hwu et al. 2000). In non-alcoholic fatty liver disease (NAFLD) mouse model, BM-MSCs were found to suppress the activation of CD4+T cells proving to be of clinical importance in the treatment of NAFLD (Wang et al. 2018a, b). In one of the studies conducted by Glennie et al., they reported BM-MSCs hindering T cell proliferation leaving activation of T cells undisturbed (Glennie et al. 2005). Other than having immunomodulatory/ immunosuppressive effects on T cell populations, BM-MSCs are also known to alter helper T cell balance. Under certain unwanted circumstances such as allergic /autoimmune diseases like asthma, T1DM or multiple sclerosis (MS), apart from modulating T cell proliferation and function, BM-MSCs are also known to shift Th1/Th2 balance and vice versa (Bai et al. 2009; Fiorina et al. 2009). Interestingly, under certain conditions such as sclerodermatous chronic GVHD and allergic airways inflammation (in mice), the contradictory result was observed. BM-MSCs exhibited a shift from the Th2/Th1 phenotype causing a shift from anti-inflammatory to pro-inflammatory phenotype (Goodwin et al. 2011; Zhou et al. 2010). BM-MSCs have also shown to modulate Th17 differentiation in favor of Treg generation or towards IL-4-producing Th2 cells (Duffy et al. 2011a; Tatara et al. 2011). Interestingly, Di lanni and group reported BM-MSCs acting as a potential homeostatic niche for T regulatory cells (Tregs) recruiting, regulating and maintaining the phenotype and function (Di Ianni et al. 2008). They demonstrated the upregulation of FoxP3 and downregulation of CD127 levels - characteristic of Tregs in BM-MSCs/T-cell co-culture. In similar lines, expansion of Tregs and suppression of cytotoxic T cells in a TGF-β1 manner in the case of human autoimmune disease – associated lung fibrosis (Liu et al. 2016). BM-MSCs were also evident in inhibiting T17 cell differentiation in IFN-γ mediated manner leading to activation of SOC3 (Liu et al. 2015). Despite the number of studies so far, it is still necessary to acquire in-depth knowledge about the complex crosstalk between BM-MSCs and T cells, for effective use of BM-MSCs in clinical settings.

5.2 BM-MSCs and dendritic cells

DC cells are the sentinel cells that act as messengers between innate and adaptive immune systems. BM-MSCs are known to alter the maturation, differentiation and functions of DCs through direct cell contact or by soluble factor (Chen et al. 2013). For example, reports have suggested suppression of increased expression levels of CD40, CD80, CD86 and HLA-DR by BM-MSCs during DC differentiation while hindering increased CD40, CD86, and CD83 expression levels during DC maturation (Zhang et al. 2004). Co-culture studies with TGF-β1 primed BM-MSCs/DCs have shown reduced expression of CD40, CD86 and MHC II and lower level of TNF-α secretion (Daneshmandi et al. 2017). Co-cultured DCs were also shown to induce lower levels of allogeneic T cell proliferation and IFN-γ release in comparison to control DCs suggesting that MSCs have a profound modulatory role on DCs. PGE-2 appears to be important in inhibiting the maturation of DCs by MSCs. In a study, BM-MSCs mediated inhibition of DC maturation was reported to be Galectin-1(Gal-1) dependent and that Gal-1 secreted by these cells had positive feedback in the respective expression levels thereby stimulating the DCs to be immunotolerant, probably via MAPK signaling to impede the role of DCs (Zhang et al. 2017). The inhibitory effect of MSCs on DCs has been implicated in various clinical conditions (detailed in later sections).

5.3 BM-MSCs and B cells

B cells are the second major players in the adaptive immune system hindering and inhibiting pathogens by secretion of specific antibodies. BM-MSCs have been reported to exert their effect on B cells by hindering the proliferation and differentiation (Corcione et al. 2006; Tabera et al. 2008). Upon BM-MSCs/B cell co-culture, BM-MSCs demonstrated a reduction in the plasma cell generation in vitro, and the same was replicated in vivo by a mechanism that involved humoral factors released by BM-MSCs along with decreased mRNA expression of B lymphocyte-induced maturation protein-1 (Blimp-1)-required for B cell activation (Asari et al. 2009). Co-cultures of BM-MSCs/B cells were reported to downregulate immunoglobulins like IgM, IgA production and the chemokine receptors like CXCR4, CXCR5, and CCR7 leaving the costimulatory molecules (CD80, CD86 and CD40) as well as the range of cytokines (TNF-α, IFN-γ, IL-4, IL-10, and IL-12) expressed and secreted by B cells unaffected by BM-MSCs (Augello et al. 2005). There are several reports suggesting hindered B cell proliferation by MSCs. For example, the proliferation of B cells has been reported to be stalled upon stimulation with anti-immunoglobulin antibodies, anti-CD40L antibody and cytokines, IL-2 and IL-4 (Corcione et al. 2006). Adding to the story, the study revealed that the immunosuppressive environment generated by BM-MSCs possibly could be due to of SDF-1-CXCR4/CXCR7 axis responsible for the secretory effects of BM-MSCs (Qin et al. 2015). Inhibition of B cells by BM-MSCs was also reported to be T-cell-mediated i.e. both presence of T cells and cell-cell communication between BM-MSCs and T cells is crucial for B cell inhibition (Rosado et al. 2015). There were contradictory results by other groups reporting the induction of B cell proliferation and differentiation by MSCs. However, recent studies have suggested that IL-35-secreting BM-MSCs might turn out to be a desirable therapeutic in treating B cell-mediated autoimmune diseases through expanding Breg cells (Cho et al. 2017). All these studies have paved the way for more intriguing questions about the exact outcome of BM-MSCs and B cell interactions.

5.4 BM-MSCs and natural killer cells

NK Cells are granular lymphocytes and are a central component of the innate immune system protecting against any infection and cancer. These cells are known to exert cytolytic effects and mediate antibody-dependent cellular cytotoxicity. Effector functions are generally mediated by immune-regulatory cytokines like IFN-γ, TNF-α, IL-10, GM-CSF and other chemokines that mediate immune response (Trinchieri 1989). The crosstalk between the BM-MSCs and NK cells referred to as crossmodulation with BM-MSCs partially impairs proliferation of NK cells while up-regulating IFN-γ and TNF-α secretion at the same time triggering the degranulation of NK cells; however, stimulated NK cells being cytotoxic induce killing of BM-MSCs via generation of reactive oxygen species (ROS) decreasing their viability and serpin B9 expression levels (Najar et al. 2018). In vivo studies in C57Bl/6 mice suggested protective action of BM–MSCs against acute liver injury via cytotoxicity attenuation and production of inflammatory cytokines by liver NK T cells in an iNOS and IDO dependent manner (Gazdic et al. 2018). Although there are several reports of immunosuppression of immune cells by MSCs, the contradictory result was reported by Cui.et al. Co-culture studies demonstrated a stimulatory effect on primary NK cells and cytokine secretion. Improvement in CCR2 mediated IFN- γ levels in patient’s NK cells was demonstrated upon co-culture with BM-MSCs and respective conditioned media and BM-MSC/NK cell co-cultures from healthy donors (Cui et al. 2016). The exact mechanism by which BM-MSCs affect NK cells remains to be elucidated. Contradictory reports urge for more investigational work in this regard.

5.5 BM-MSCs and TLR3/4

BM-MSCs have shown to express a class of proteins called toll-like receptor (TLR) proteins playing a key role in the innate immune system. These proteins have been found to aid in proliferation, migration and differentiation of BM-MSCs in vitro (Tomchuck et al. 2008). TLR3 is known to induce migration in BM-MSCs under stress conditions. Emerging studies on TLRs have revealed their effect on MSCs (Pevsner-Fischer et al. 2007). Being expressed on BM-MSC in abundance, TLRs on ligation induce stimulation of pro-inflammatory signals thereby preventing inhibition of T cell proliferation, probably via downregulated Notch ligand by BM-MSC (Liotta et al. 2008; Tomchuck et al. 2008).

6 Immunomodulation in various clinical conditions

One of the initial illustrations of immunomodulatory/immunoregulatory properties of BM-MSCs in in vivo condition were for skin transplantation in a baboon model, in which, administration of BM-MSCs led to a prolonged skin graft survival. The immunomodulatory effects of BM-MSCs currently being explored in various clinical trials are enlisted in the clinical trials website by the National Institute of Health (http://clinicaltrails.gov). The profile of BM-MSCs (summary listed in table 2), makes them immune elusive and thus desirable candidate for cellular therapies for numerous medical situations (enlisted in table 3). We present a brief review of some of the common clinical conditions in which the immunomodulatory properties of BM MSC have been put to best use.

Table 2 Summary of secretory and hypoimmunogenic profile of MSCs
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Table 3 Clinical trials using Bone marrow mesenchymal stem cells (BM-MSCs) as immunosuppressants (source: http://clinicaltrails.gov)
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6.1 Graft-versus-host disease

Graft-versus-host disease (GVHD) is a complicated condition caused after allogeneic transplants where donor T cells react against host tissues that can potentially be life-threatening. In humans, the success rate of BM transplantation across major histocompatibility complex (MHC) barriers is lowered by graft rejection and incomplete T cell recovery. BM-MSCs suppress the allogenic T cell response by secretion of TGF-β suggesting that pretreatment of BM-MSCs might be useful in the prevention of GVHD in HLA-mismatched BM transplantation and further donors for hematopoietic stem cells could be selected with greater potentials (Tian et al. 2008). It was also demonstrated that the anti-proliferative activity of BM-MSCs is due to its effect on T cell proliferation rather than on its effector function (Joo et al. 2010; Zhou et al. 2010). New strategies of GVHD prophylaxis include the infusion of expanded MSCs and downregulation of host antigen-presenting cells. Effective treatment using third-party haploidentical BM-MSCs in patients with severe GVHD lead to numerous phase I and II trials which further demonstrated clinical benefits of BM-MSC therapy in GVHD (Le Blanc et al. 2008, 2004). BM-MSC in combination with Tregs provides a reciprocal immunomodulatory effect coupled with mutual regulation of Th1/Th2 and Th17/Treg cells in a murine GVHD model (Lim et al. 2014). In 2016, a pilot study conducted in Turkey reported allogeneic hematopoietic stem cell transplantation (allo-HSCT) to treat refractory acute GVHD in 33 pediatric patients. About 68 doses of BM-MSCs were infused into the patients out of which twelve patients developed chronic GVHD; eight of them were alive, with five having extensive disease and three having limited disease suggesting BM-MSCs to be benign and effective treatment opportunity for pediatric patients with steroid-refractory acute GVHD. But the efficacy at the same time remains limited (Erbey et al. 2016). Despite the efficacy of allo-HSCT, the procedure is still associated with high toxicity in patients with refractory GVHD, BM-MSCs being the new mode of therapy in the context of allo-HSCT. There were reports demonstrating BM-MSCs treated GVHD having a higher CD4+/CD8+ T cell ratio, higher levels of T cell receptor rearrangement excision circlets and increased frequency of Tregs, compared to pre-treatment and non-treated GVHD patients (Liu et al. 2015). Although the emerging evidence is promising, more robust data from larger clinical trials with predictable insight of the biology of BM-MSCs would possibly pave the way for considering it as part of the treatment protocols.

6.2 Autoimmune diseases

These conditions arise due to dysfunction of the body’s immune system where recognition between self and non-self is lost resulting in attacking own cells/tissues. Almost 50 years ago the importance of autoimmunity and the underlying principles was recognized following Macfarlane Burnett’s hypothesis of the ‘forbidden clone’. The major causes of autoimmunity continue to be an environmental trigger like infections or genetic predisposition. Due to their immune-regulatory properties, BM-MSCs are being tested in various auto-immune diseases for their efficacy and safety in alleviating the condition. We present the review of some of the conditions in which it has been extensively studied.

6.2.1 Systemic lupus erythematosus (SLE)

SLE is an inflammatory disease marked by the existence of self-reactive T and B lymphocytes, with polyclonal stimulation of B cells and plasma cells producing autoantibodies subsequently with the release of cytokines. In 2007, Sun and coworkers reported abnormality in BM-MSCs in patients with SLE suggesting an important role that BM-MSCs might play in SLE pathogenesis in these patients (Sun et al. 2007). Many reports reported the efficacy of MSCs and it’s secretome in SLE pathogenesis. For example, MSCs were found to exert its effect through secreted paracrine factors like extracellular microvesicles as important mediators of BM-MSC therapy (Figueroa et al. 2014). Reports from combined transplantation of autologous hematopoietic SC and allogenic BM-MSC suggested an increase in the population of Tregs in SLE with refractory lupus nephritis and leukopenia (Wang et al. 2015). Infusion of BM-MSCs suppressed follicular helper T-Cell development thereby alleviating autoimmune nephritis in a lupus model (Jang et al. 2016). A recent long-term follow-up study of allogenic BM-MSCs transplantation has reported overall survival rate was 84% and demonstrated allogenic BM-MSC transplantation is safe and stemmed in a prolonged clinical diminution in SLE patients (Wang et al. 2018a, b). Although numerous works have been done on understanding the immunomodulatory role of BM-MSCs in SLE, the complete understanding remains unclear.

6.2.2 Type I diabetic mellitus (T1DM)

T1DM is a chronic auto-immune disorder in which the immune system is activated to destroy the insulin-producing β-cells of the pancreas. BM-MSCs have been reported to play an evident role in the treatment regimen of T1DM. Some of the earlier reports demonstrated the differentiation of BM-MSCs into insulin-producing cells using numerous transcription factors associated with the β-cell developmental pathway upon culture in a suitable niche (Moriscot et al. 2005). There is also evidence from an in vivo experiment that the mouse BM-MSCs, can be differentiated into functional β-cells insulin gene (Ianus et al. 2003). In similar lines, insulin gene transfected BM-MSCs were reported secreting insulin, offering a different way to deal with β-cell shortage for T1DM therapy (Lu et al. 2006). With respect to immunoregulatory properties, although the underlying mechanism of tissue regeneration was not known, cytokines and growth factors may exert their effects via a combination of bioactive and immunoregulatory factors. Importantly, these growth factors have been shown to promote islet survival and enhance β-cell function in several published studies (Lim et al. 2009; Suarez-Pinzon et al. 2005). BM-MSCs inhibited immune response mediated by T cells against novel β-cells which could be one of the suitable methods for T1DM treatment (Li and Ikehara 2014). Antidiabetic effect of BM-MSCs is also believed to be due to the restoration of the equilibrium between Th1 and Th2 immunological responses in addition to the pancreatic microenvironment modification (Ezquer et al. 2012). Recently a study reported decreased daily dosage level of insulin within 3 months after transplantation of autologous BM-MSCs in 5 patients (Ulyanova et al. 2019). Although there are promising results demonstrating possible efficacy of BM-MSCs in preserving β-cell function in some T1DM patients, confirmed by the reduced insulin doses, improved HbA1c levels and higher C-peptide level, long term effectiveness of BM-MSCs for T1DM management remains doubtful (Gazdic et al. 2018).

6.2.3 Multiple sclerosis (MS)

Multiple Sclerosis is a chronic immune-related disease of the central nervous system where the immune cells attack and damage the myelin sheath of nerves causing loss of communication within the brain and between brain and rest of the body. Due to their immune suppressive/immunoregulatory ability and repair/regenerative ability, BM-MSCs have been studied in various neurodegenerative diseases like MS. BM-MSCs have been administered to small series of patients who were tested under a variety of clinical settings have supported their safety and potential efficacy with signs of immunomodulation (Bonab et al. 2012; Cohen 2013; Karussis et al. 2010). Autologous BM-MSCs from patients with MS exhibit similar properties as those from volunteers, in the context of immunosuppressive ability, proliferation, differentiation and phenotype in vivo (Rice et al. 2010). Successful attempts were reported by a study conducted aiming at investigating the efficacy and clinical safety of transplanted (autologous) MSCs into MS patients (Karussis et al. 2010). International experts in MS and SC, in association with immunologists, designed the “International Stem Cells Transplantation Study Group” (IMSCTSG) intending to accomplish an agreeable procedure on the practice of MSCs for MS treatment- procedures for cell culture and treating patients (Freedman et al. 2010). In an open-label study conducted by Bonab and coworkers, 25 patients who were recruited with progressive MS and administered with a single intrathecal injection of autologous BM-MSCs were found to have improvement in the disease with no severe adverse effects (Bonab et al. 2012). A randomized placebo-controlled phase II trial, where patients were infused with MSCs intravenously, exhibited a lesser proinflammatory T cell profile, subsequently from reduced IFN-γ levels and IL-17-producing CD4+ T cells intensity, in addition to reduced Th1/ Th17 ratio signifying a persisting effect of MSCs (Llufriu et al. 2014). Another open-label prospective phase I/IIa clinical study using BM-MSCs followed by respective conditioned media results showed that the protocol was safe and feasible with possible efficacy (Syková et al. 2017). A very recent study showed that aging restricts the potential of BM-MSCs in supporting the oligodendrocytes generation and consequently inhibiting their ability to enhance the generation of myelin-like-sheaths (Rivera et al. 2019). These findings may impact the design of therapies using autologous BM-MSCs in older MS patients. To date, cell therapy with BM-MSCs has been, overall, well-tolerated and safe.

6.2.4 Rheumatoid arthritis (RA)

RA is an autoimmune disorder characterized by abnormal leukocyte permeation, and proteases within the joint, persistent inflammation of the synovium, ultimately leading to bone and cartilage destruction. Transplantation of human BM-MSC in collagen-induced arthritis (CIA) mice resulted in reduced GM-CSF expressing CD4+ T cells in the spleen and blood, significant in RA pathophysiology and induced a regulatory phenotype in Th17 cells thereby reducing the Th1:Th17 ratio along with significant reduction in TNF-α serum levels. In the co-culture system, BM-MSCs have also been reported to repress follicular Th cell differentiation in CIA mice hindering B cell differentiation resulting in hindered B cell differentiation (Qin et al. 2015; Rosado et al. 2015). BM-MSC inhibits osteoclast-mediated bone resorption leading to bone loss followed by a reduction in the production of inflammatory cytokines and the induction of Tregs promoting osteoclastogenesis.BM-MSCs inhibit osteoclastogenesis either by producing osteoprotegerin or through interacting with the precursors, via CD200/CD200R communication (Varin et al. 2013). The secretome of BM-MSCs has also been reported in treating the disease. BM-MSC derived EVs have been reported in reducing inflammation and inducing pathological changes by influencing Bregs (Cosenza et al. 2017). In summary, human trials indicate BM-MSCs to be beneficial in RA treatment, nevertheless more multicenter clinical studies are needed for further evidence.

7 Future directions

Because of the ease of access, well-identified phenotypic characteristics, ubiquitous presence in most tissues of the body, longevity and hypoimmunogenecity, the new tools of gene editing and gene therapy are being applied to BM stromal cells. More preclinical studies are warranted to standardize the dose, route of application, long-term survival of cells, the sustainability of hypoimmunogenecity in diverse host conditions, etc., before they can gain popularity in clinical practice.

8 Conclusion

BM-MSCs because of their ease of isolation, in vitro expansion, and capability of differentiation into multiple lineages have gained much importance in the field of cell therapy and regenerative medicine. Also, BM-MSCs display immunomodulatory and immunosuppressive property either by cell-cell communication or by soluble factors. They are known to suppress the proliferation of T cells, B Cells, NK cells, upregulate Tregs population and need to be activated in order to exert its immunoregulatory effect. This activation requires the presence of proinflammatory cytokines from T cells, NK cells and macrophages suggesting there is bi-directional communication between MSCs and the immune cells. While the BM-MSCs have found its way to clinical application, there is mounting evidence that the secretome and the extracellular vehicles could possibly pave the way for translational research in the future.