The potential role of mesenchymal stem cells (MSCs, also called mesenchymal stromal cells) in endogenous repair and cell-based therapies for acute kidney injury is intensively studied. Preclinical studies indicate that administered MSCs both ameliorate renal injury and accelerate repair. These versatile cells home to sites of injury, where they modulate the repair process. The mechanisms responsible for the protective and regenerative effects of MSCs involve paracrine and endocrine effects, including mitogenic, antiapoptotic, anti-inflammatory and angiogenic properties. Given positive preclinical results, together with the strong clinical need for novel therapies to treat acute kidney injury, the ease of isolation and expansion of MSCs and encouraging preliminary clinical trial results in other fields, there is great interest in MSC-based approaches for the treatment of both acute and chronic human kidney diseases. This chapter summarizes current knowledge and clinical applications in this rapidly moving field and identifies gaps in our understanding of MSC biology that will need to be filled to realize the potential of MSC-based therapies to treat human kidney disease.

Introduction

Stem cells play fundamental roles in the self-renewal of adult tissues throughout life. Some tissues are characterized by ongoing loss of cells, including the hematopoietic system, intestine and skin, and adult stem cells are responsible for replenishing these cells to maintain tissue homeostasis. Other organs, such as kidney or lung, have a much lower rate of cellular turnover, but are capable of proliferating and repairing after an injury stimulus . While epithelial stem cells can be recruited, proliferate and differentiate to reconstitute some injured tissues, it remains unclear whether the kidney follows this paradigm for epithelial stem cell-based homeostasis and repair after injury . Basal tubule cell turnover in kidney is exceedingly low, and the turnover that can be detected has been proposed to occur by division of terminally differentiated tubular epithelial cells . Soon after injury, by contrast, there is diffuse tubular cell proliferation, potentially reflecting the intrinsic ability of surviving epithelial cells to adapt to the loss of neighboring cells by dedifferentiating and proliferating and ultimately replacing the cells that have died as a result of the insult. Based on the high proliferative capacity of injured kidney, one longstanding model holds that tubular cells themselves are the source of nephron repair .

Studies on the role of bone marrow-derived cells (BMDCs) initially challenged this model of dedifferentiation followed by proliferation and redifferentiation of existing tubular cells after injury. Bone marrow contains at least two populations of stem cells in addition to stromal cells. The hematopoietic stem cell (HSC) gives rise to all differentiated blood cell types, and mesenchymal stem cells (MSCs) that give rise to mesenchymal cell types including chondrocytes, osteocytes and adipocytes. While it has long been appreciated that bone marrow-derived inflammatory cells home to injured kidney, recent studies have suggested that BMDCs directly participate in renal injury and repair. MSCs in particular have been reported to protect against experimental renal injury as well as accelerate the repair process in rodent models. As will be reviewed, some reports indicated that the MSCs directly replace dead tubular epithelial, whereas other observations suggest that MSCs regulate the endogenous reparative machinery without transdifferentiating into tubular cells overall, the emerging body of evidence describing MSC modulation of acute kidney injury (AKI) has stimulated a reappraisal of the cellular mechanisms behind renal injury and repair as well as generated considerable excitement at the prospects for novel cell therapies to treat human kidney diseases.

The Mesenchymal Stem Cell

MSCs are an undifferentiated, adult cell type that can be isolated from a variety of tissues but primarily bone marrow stroma. The embryonic lineage of these cells is mesodermal, from mesenchymal cells that give rise to connective tissues such as bone, cartilage and fat as well as blood supply-related organs such as the vasculature and hematopoietic system. The International Society for Cellular Therapy has proposed a set of standards to define human MSCs for scientific and preclinical studies, including adherence to plastic in culture, fibroblastoid appearance, multipotentiality (ability to differentiate into different cell types), expression of typical surface markers such as CD73, CD90 and CD105, and the absence of expression of hematopoietic lineage markers . There is no definitive proof that MSCs are a clonal, self-renewing stem cell, and for this reason many suggest that MSCs refer to “multipotent mesenchymal stromal cells” .

MSCs not only reside in bone marrow but have also been isolated from skeletal muscle , adipose , umbilical cord , dental pulp , amniotic fluid and other sources. Very recent reports have suggested that MSCs may reside in capillary and microvessel walls throughout the body, sharing markers and characteristics of the vascular pericyte . The finding that purification of pericytes through sorting (CD146 ⁺ , CD34 ⁻ , CD45 ⁻ , CD56 ⁻ ) with subsequent in vitro expansion leads to clones of multipotent cells led Caplan to speculate that all MSCs are pericytes . The pericyte phenotype is characterized by expression of CD146, NG2 and platelet-derived growth factor (PDGF)-Rβ and the absence of hematopoietic, endothelial and myogenic markers, as well as multilineage differentiation ability. The attraction of the hypothesis that MSCs are natively associated with blood vessel walls is that it helps to explain why MSCs have been isolated from so many different organs . However, it is not yet clear exactly which subset of perivascular cells contain MSCs and it remains possible that MSCs may derive from other sources.

The functional properties of MSCs make them unique. These multipotent stem cells can differentiate to cells of the mesenchymal lineage such as osteocytes, adipocytes and chondrocytes and potentially other cell types. Directed differentiation can be achieved by culturing MSCs in defined conditions . MSCs are easily cultured, which distinguishes them from embryonic stem cells (which generally require feeder cells and special growth medium) and other adult stem cells. MSCs can be expanded, explaining why they are among the first cells to be used for cellular therapies in humans, since it is not difficult to obtain clinically useful numbers of cells. Finally, MSCs possess immunomodulatory properties that have made them especially attractive for potential use in treating human disease characterized by autoimmunity or inflammation, including graft versus host disease, multiple sclerosis and Crohn’s disease .

Amniotic Fluid-derived Stem Cells

The isolation of multipotent stem cells from amniocentesis specimens, termed amniotic fluid-derived stem cells (AFSs), offers a new source of stem cells for use in cellular therapy . AFSs represent about 1% of all amniotic fluid cells and are characterized by expression of the cell surface marker c-kit, as well as other surface antigens also expressed by MSCs such as CD73, CD90 and CD105. Like MSC, they do not form teratomas in vivo, which distinguishes both of these stem cells from embryonic stem cells. AFSs have two important differences from MSCs. First, they are significantly more broadly multipotent than MSCs, and may in fact be pluripotent. Second, AFSs are clonal and therefore are a true stem cell population. Initial studies suggest these cells, like bone marrow-derived MSCs, ameliorate AKI . Whether the properties of AFSs will make them a better candidate for cellular therapies in kidney injury needs to be investigated; however, their accessibility makes them a very attractive candidate for regenerative medicine . The prospect of banking amniocentesis specimens for future AFS isolation and use in autologous cell therapies, or matching histocompatible donor cells with recipients, represents an important advance in regenerative medicine.

Bone Marrow Plasticity and Renal Repair

The current interest in MSCs for treatment of AKI grew in part from the observations made by Petersen et al. and Theise et al. that BMDCs could develop into hepatocytes. This finding, later reported in humans , led to intensive research on the plasticity of BMDCs. Evidence for engraftment of BMDCs was soon reported in other tissues including lung, gastrointestinal tract and skin. Krause et al. demonstrated that a single transplanted HSC could provide hematopoietic reconstitution for a lethally irradiated recipient, and that this single hematopoietic cell could also engraft non-hematopoietic tissues including lung, liver, gastrointestinal tract and skin . These surprising results were followed by studies from Poulsom et al. and Gupta et al., who examined renal biopsies from male patients transplanted with female kidneys. Both groups reported the presence in the allografts of Y-chromosome-positive tubular epithelial cells, varying from less than 1% up to 20% of cells examined , with similar results found in mouse .

Follow-up studies have led to a re-evaluation of the physiological relevance of the initial observations concerning BMDCs transdifferentiating into renal epithelia. It has been proposed that the early results could be due to cell fusion or possible artifactual detection of lineage markers. The inability to repeat some of these findings in other laboratories has also contributed to the debate . Not all issues have been resolved, but several conclusions are possible. The method of marking and detecting the bone marrow lineage is critical. Bacterial β-galactosidase transgene activity, in particular, may be problematic owing to high expression of endogenous kidney β-galactosidases and possible leakage of the enzyme by damaged cells, with subsequent uptake by neighboring cells. Green fluorescent lineage markers, such as enhanced green fluorescent protein (GFP), are also subject to misleading artifacts owing to the high intrinsic autofluorescence of the postischemic kidney. This autofluorescence can cause misinterpretation of fluorescent immunostaining. High-resolution marker detection in kidney sections is especially important, with three-dimensional (3D) deconvolution or confocal microscopic techniques required to distinguish between closely apposed and overlying cells and nuclei . Bone marrow-derived leukocytes traffic to the renal interstitium after renal injury, and a superimposed leukocyte nucleus may be mistaken for an epithelial cell nucleus unless such high-resolution imaging is utilized. Cell overlay and intrinsic autofluorescence have also complicated the interpretation of BMDC contribution to myocardial regeneration, emphasizing the challenge of tracking cell fate in vivo, particularly in injured tissues .

Studies utilizing mice with bone marrow transplants harboring several different lineage markers have led to the conclusion that BMDCs only rarely contribute to the renal epithelial lineage under physiological conditions (at most 1% but probably much less) . Using chimeric mice in which GFP-positive bone marrow was transplanted to a GFP-negative recipient, Duffield et al. performed ischemia–reperfusion injury (IRI) and tracked the fate of the GFP-positive cells during injury and repair . While they did observe an influx of GFP-positive cells into kidney, these were almost exclusively interstitial cells, 99% of which were leukocytes. This observation is consistent with the important role of interstitial inflammation in the pathogenesis of AKI . Similar results were found using LacZ as a fate marker for bone marrow cells or sex-mismatched transplants utilizing Y-chromosome as a marker for transplanted cells. In the case of Y-chromosome analysis, it is notable that several putative examples of tubular epithelial cells positive for the Y-chromosome were observed by standard fluorescence microscopy, but with high-resolution deconvolution microscopy, these were revealed to be leukocytes overlying epithelial cell but within the interstitium.

Cell fusion is another possible explanation for earlier results and this is emphasized by a study from Grompe and co-workers that convincingly showed a 20–50% fusion of tubular epithelia with BMDCs under long-term and intense genetic pressure . Li et al. employed an elegant fate-mapping technique to quantitate the degree of fusion after IRI . They started with a transgenic mouse that expressed Cre recombinase only in renal epithelial cells: the Ksp–Cadherin–Cre (Ksp-Cre) driver line. Next, they transplanted bone marrow from donor mice that expressed a reporter gene, EYFP (enhanced yellow fluorescent protein) only after Cre-recombinase-mediated recombination of a LoxP-flanked stop sequence. In resulting mice, any tubular cell that activated expression of EYFP was derived from bone marrow. Next, they performed ischemic injury, and assessed gain of EYFP expression along with ploidy in kidney. After 28 days, they found a substantial number of EYFP-positive immune cells in the renal interstitium, but only very rare EYFP-positive tubular epithelial cells at a frequency of 0.066% of total tubular cells. The authors concluded that cell fusion occurs between BMDCs and epithelia, that injury is required for fusion and that these events are very rare.

Mesenchymal Stem Cells Ameliorate Renal Injury and Accelerate Repair

Although endogenous BMDCs do not directly replace renal epithelia during renal repair, several lines of evidence indicate that exogenously administered MSCs do modulate the kidney repair and regenerative response. Intravenous injection of the lineage-negative bone marrow fraction before injury, part of which contains MSCs, blunted the initial rise in blood urea nitrogen (BUN) after IRI , whereas whole bone marrow had no protective effect . Injection of purified MSCs almost completely protected against cisplatin-induced rise in BUN, whereas injection of purified HSCs had virtually no protective effect . Similar protection from injected MSCs was found in a glycerol-induced pigment nephropathy model and in a model of IRI . Importantly, Westenfelder and colleagues have shown that infused MSCs enhance recovery of rats subjected to IRI even if administered 24 h after the injury, suggesting active participation of these cells in the repair process . Taken together, there is good evidence that administered MSCs both protect against AKI in toxic and ischemic rodent models and accelerate the recovery phase .

Efficacy of Mesenchymal Stem Cell Therapy in Chronic Kidney Diseases

Accumulating evidence suggests that MSC therapy is efficacious not only in the acute injury setting, but also in chronic, progressive kidney diseases. The Kalluri and Cook laboratories have independently used the Col4a3 ^−/− model of progressive glomerular disease to determine whether administered MSCs might rescue the genetic defect. Both found that transplantation of wild-type MSCs into irradiated Col4a3 ^−/− recipients led to partial restoration of type IV collagen α3 chain expression in glomerulus, improved glomerular histology, reduction in proteinuria and improved overall kidney histology . Transplantation of bone marrow from Col4a3 ^−/− donors did not ameliorate disease, suggesting that BMDCs homed to the glomerulus, took up residence and secreted wild-type type IV collagen. The precise identity of the bone marrow-derived glomerular cells (podocyte, mesangial cell or other) remains a subject of investigation. Subsequently, Katayama et al. found that irradiation alone ameliorated kidney disease in the same model, suggesting that the BMDCs may have little to do with the observed effects . In a follow-up study, LeBleu found that transplantation of wild-type marrow also improved survival in a similar Col4a3 knockout model , in contrast with Gross and co-workers, who found reduced fibrosis but no difference in mortality . Most importantly, though, in the LeBleu study, irradiation was not required to rescue the phenotype, confirming that the infused cells were actively participating in glomerular repair. Collectively, these studies demonstrate that the notion of stem cell therapy for Alport’s disease, whether MSC or embryonic stem cell, remains a promising one, but that much work is left to do in order to understand the optimal cell source, delivery method and most importantly mechanism of the observed effects.

MSCs may have therapeutic application in other chronic, fibrotic kidney diseases. Using the remnant kidney model, intravenous injection of MSCs in rats every other week resulted in a modest protection of renal function decline at 8 weeks, with reduced fibrosis readouts such as picrosirius red staining, collagen I production and α-smooth muscle actin (α-SMA) expression . Notably reduced were measures of inflammation, suggesting that it was the immunosuppressive effects of MSCs that mediated this antifibrotic effect. However, renal function was equal by 12 weeks in placebo versus MSC-treated groups, suggesting that the anti-inflammatory effects of MSCs may result in only transient protection from progressive renal fibrosis. In a shorter study using the same remnant kidney model, the Noronha group injected MSCs in the subcapsular space, and observed decreased blood pressure, proteinuria and histology scores for fibrosis at 30 days . Longer periods were not investigated. Ezquer et al. examined whether intravenous administration of MSCs might be therapeutic in a diabetic nephropathy model. One month after streptozotocin injection to induce diabetes, these investigators injected C57BL/6 mice with vehicle or two doses of 0.5 × 10 ⁶ MSCs. Over the next 3 months, vehicle-injected mice developed progressive albuminuria, mesangial expansion and glomerulosclerosis, all of which were substantially improved in mice that received MSCs . Both groups had equivalent hyperglycemia and hypoinsulinemia, however, indicating that the mechanism did not involve an MSC-mediated effect on pancreas regeneration. Moreover, GFP-expressing MSCs persisted in kidneys at 3 months after injection, albeit at low levels, suggesting possible ongoing secretion of renotropic factors.

Do Exogenous Mesenchymal Stem Cells Directly Engraft into Injured Tubules?

Morigi et al. and Herrera et al. reported that exogenous MSCs can engraft into injured tubules, and proposed that the ability to transdifferentiate explained their protective effect . Yokoo et al. directly injected exogenous MSCs into developing kidney with subsequent embryo and organ culture and observed MSC incorporation into glomerulus, tubule and interstitium, findings that seem to support the possibility of direct engraftment . In contrast, studies by Lin et al. and the present group showed protection from injury by exogenous MSCs but very little or no tubular incorporation. Some of the discordant findings may be explained by different injury models and protocols, as suggested by Broekema et al. ; however, the same caveats described previously regarding proof of tubular incorporation of BMDCs also apply to studies of injected MSCs. The nature of the MSC marker, careful 3D microscopic analysis and the possibility of cell fusion all need to be taken into account. It is relevant in this regard that in a follow-up study, Herrera reported much lower tubular incorporation of MSCs (about 2.5%) compared to an earlier report (about 20%) using the same glycerol-induced renal injury model, but a different fluorescence-based cell tracking method of injected MSCs .

The bulk of available data indicates that the effects on renal repair of exogenous MSCs are not explained by direct repopulation of the tubule. The timing of renal epithelial cell proliferation, which is dramatically increased within 24–48 h, appears to be too rapid to be explained by transdifferentiation of extrarenal cell types into epithelial cells. In most studies the protective effect of injected MSCs is observed within 24–48 h. When careful lineage analysis has been done, the numbers of MSCs or BMDC-derived epithelial cells appear to be so low (1% or less) that they could not have functionally contributed to repairing the nephron, at least by direct engraftment. Vogetseder et al. have argued that in the uninjured kidney, the small amount of epithelial proliferation present occurs by division of terminally differentiated cells .

To test definitively whether an endogenous, non-epithelial stem cell population might contribute to the epithelial lineage during mammalian renal repair, a comprehensive fate-mapping study of renal epithelial cells during renal IRI was performed. All mesenchyme-derived renal epithelial cells were genetically labeled using a Cre/Lox strategy. The Six2 gene is expressed exclusively in metanephric mesenchyme cells fated to become renal epithelia , and a transgenic mouse in which the Six2 promoter drives expression of a GFP–Cre recombinase fusion protein (the Six2–GC mouse) was crossed against two different reporter mice, the Rosa26-LacZ (R26R) reporter, and the ACTB-Bgeo,-DsRed.MST reporter (Z/Red). Because the Six2 gene is active very early in nephrogenesis, recombination efficiency was high and 95% labeling of all tubular epithelial cells derived from the metanephric mesenchyme was achieved (collecting duct epithelia are derived from the ureteric bud, and therefore not labeled in this model) . Since interstitial cells and non-renal cells are not labeled, after a cycle of injury and repair, dilution of the fate marker would indicate contribution to the epithelial lineage by unlabeled cells. If repaired tubules still express the fate marker, by contrast, then repairing epithelial cells originated from within the tubule.

Close inspection of kidney sections confirmed that no interstitial cells were labeled, with either LacZ or with red fluorescent protein (RFP). GFPCre fusion protein expression was undetectable after the completion of nephrogenesis (P3–5), whether assessed by epifluorescence or antibody-based detection of GFP (the GFPCre fusion protein retains GFP fluorescence), Six2 mRNA or Six2 protein using a specific antisera. (Since GFPCre expression is regulated by the Six2 promoter, the GFP expression pattern mirrors expression of endogenous Six2 mRNA and protein.) Mice were subjected to renal IRI to trigger the proliferative response. Two days after injury, 47.4% of cells in the outer medulla expressed the proliferation marker Ki67, and these cells coexpressed RFP ( Fig. 9.1 ). Many tubules had flattened epithelial cells characteristic of the dedifferentiated state, and these cells also expressed Ki67, indicating the cells had re-entered the cell cycle, and RFP. When mice were injured and given an injection of bromodeoxyuridine (BrdU) once daily for 7 days, 66.9% of outer medulla epithelial cells had incorporated BrdU, compared with 3.5% in uninjured, control kidneys. Despite this robust proliferation, there was no dilution of the fate marker in kidneys that had been allowed to repair for 15 days. Before injury 94.3 ± 3.7% of outer medullary epithelia were RFP positive, and after repair 94.4 ± 2.4% expressed RFP, with similar results calculated for LacZ as the fate marker .

Kidney repair after ischemia–reperfusion injury (IRI) occurs by proliferation of surviving epithelial cells. Section from a kidney of a mouse with red fluorescent protein (RFP) expression in all epithelial cells 48 h after IRI shows that flattened, dedifferentiated epithelial cells have re-entered the cell cycle, as judged by expression of nuclear Ki67 (arrows). Because there was no dilution of the RFP fate marker, mesenchymal stem cells do not directly contribute to epithelial repair after IRI . Please see color plate at the end of the book.

If the GFPCre fusion protein were re-expressed in epithelial cells after injury, then a non-labeled interstitial cell that had migrated into the damaged tubule might also be induced to express GFPCre, and thus activate expression of either RFP or LacZ, compromising our ability to detect a dilution of the fate marker. However, re-expression of the transgene, as assessed by sensitive GFP immunofluorescence, was not detected despite very robust GFP fluorescence in the cap mesenchyme of P1 kidneys from Six2-GC mice, a stage where Six2 is still expressed. The researchers were also unable to detect Cre mRNA after injury by qualitative reverse transcription polymerase chain reaction, and endogenous Six2 protein was not detected in adult kidney after injury using a specific anti-Six2 antibody.

Thus, there is now consensus that both endogenous BMDCs and exogenously administered MSCs can give rise to renal epithelial cells only rarely, if at all, and that cell fusion may underlie some of these events. The rarity of transdifferentiation to kidney epithelia indicates that direct tubule repopulation by BMDCs or administered MSCs does not have physiological relevance to renal repair from injury in vivo.

Homing of Exogenous Mesenchymal Stem Cells

The mechanisms by which MSCs promote kidney repair remain unclear but an important aspect of the therapeutic effects of MSCs appears to be their ability to home to injured organs. Lange et al. labeled exogenous MSCs with iron-dextran and found these cells located primarily in the renal cortex after IRI in the rat, as assessed by magnetic resonance imaging. These cells remained associated with kidney 3 days after IRI, and histologically they were localized to glomerular capillaries . In a more detailed analysis, fluorescently labeled MSCs were localized by two-photon microscopy to both glomeruli and peritubular capillaries within 10 min of intra-arterial injection into rats subjected to IRI 24 h before . The relative importance of MSCs homing to glomerular versus peritubular capillaries is not known. MSCs have been detected in both compartments in both acute and chronic injury models . Either location may be efficacious, with peritubular MSCs poised to signal to adjacent tubular epithelia and glomerular MSCs potentially able to secrete factors that are filtered into the tubular lumen, where they may bind to and directly regulate damaged epithelial cells. Another unresolved question is whether MSCs bound to the renal microvasculature are capable of migrating into the renal interstitium. Although no direct evidence supports such a possibility at present, it has not yet been examined rigorously.

Recent studies have begun to dissect the signals that regulate MSC homing. Inflammation improves engraftment efficiency of infused MSCs, suggesting the MSC–endothelial cell interactions may be important in homing. Indeed, blocking β ₁ -integrin expressed on MSCs reduced engraftment of MSCs in ischemic myocardium, suggesting that MSC recognition of the endothelial cell VLA-4 adhesion molecule via β ₁ -integrin was required for engraftment . P-selectin and vascular cell adhesion molecule (VCAM) have additionally been shown to be critical components of the initial steps of interaction between MSCs and endothelium. Using a parallel plate flow chamber, Rüster et al. were able to block MSC rolling and adherence to endothelium by preincubating endothelial cells with either anti-P-selectin or anti-VCAM antibodies, for example . Support for a central role for VLA-4–VCAM-1 interaction in mediating MSC–endothelial interactions has also come from studies of the firm adhesion of MSCs to activated endothelium under shear stress conditions . It is clear that molecular interactions guide MSC binding to endothelium and tissue engraftment, rather than trapping in microvasculature, but elucidating the details of this process remains a challenge.

Chemotaxis of MSCs to sites of inflammation is also an area of intensive investigation at present. A number of candidate mediators has been identified, with one attractive candidate being the chemokine stromal cell-derived factor-1 (SDF-1). SDF-1 binds exclusively to its receptor CXCR-4, is expressed in the distal tubule and is upregulated after renal injury . CXCR4 is expressed in MSCs. Its expression is upregulated by hypoxia and the SDF-1/CXCR4 pair is known to regulate HSC migration. Furthermore, hypoxic preincubation of MSCs appears to increase engraftment in vivo . Another promising candidate as a regulator of homing is platelet-derived growth factor (PDGF), which is secreted from the basolateral aspect of human epithelial cells . Cultured MSCs express PDGF receptors and potently migrate in response to exogenous PDGF. This migratory response is enhanced by preincubation of MSCs with tumor necrosis factor (TNF) . Recently, a new candidate for MSC homing has emerged in CD44, which is expressed on MSCs and required for renal localization of injected MSCs after glycerol-induced renal injury. The receptor for CD44, hyaluronic acid, is upregulated in kidney after injury, and CD44-negative MSCs show reduced migration to injured kidney as well as decreased protection from injury . Elucidating the precise mechanisms controlling MSC migration to injured kidney may have important consequences for human therapy, since effective delivery of these cells to damaged tissue may be critical for therapeutic efficacy .

Evidence that Mesenchymal Stem Cells Repair Kidney by Paracrine and Endocrine Mechanisms

Since MSCs do not directly repopulate the repairing tubule then paracrine and/or endocrine mechanisms must explain their therapeutic effects in AKI. Similar mechanisms are likely to underlie some or all of the therapeutic effects of MSCs in glomerular diseases, although this remains controversial. Given the importance of inflammation in the pathophysiology of AKI it is very important to consider the immunomodulatory properties of MSCs and the role they may play in renoprotection . MSCs are immunologically privileged and allogeneic MSCs do not induce a proliferative T-cell response. The mechanisms for this tolerance include low surface expression of both major histocompatibility complex (MHC) class I and II molecules, lack of expression of major costimulatory molecules such as CD40, CD80 and CD86, and direct inhibition of dendritic cell alloantigen-induced differentiation and activation, among others . MSCs also exert anti-inflammatory influences on T cells. Coculture of MSCs with Th1, Th2 or natural killer (NK) cells decreases their secretion of proinflammatory cytokines such as TNF-α and interferon-γ (IFN-γ) and increases their secretion of suppressive and tolerance-promoting cytokines such as interleukin-10 (IL-10); this effect is largely mediated by MSC production of the eicosanoid prostaglandin E ₂ (PGE ₂ ) . T cells play important roles in both immune-mediated and ischemic kidney disease, so the ability of MSCs to regulate T-cell function is likely to be relevant for their therapeutic effects in AKI . In support of this notion, Semedo et al. recently measured higher levels of anti-inflammatory cytokines in kidney extracts from MSC-treated animals after IRI . Proinflammatory stimuli such as IFN-γ promoted the immunosuppressive effects of MSCs, including protection from NK cell-mediated cytolysis, enhanced hepatocyte growth factor (HGF) and transforming growth factor-β (TGF-β) secretion and induction of indoleamine 2,3-dioxygenase (IDO), an enzyme that inhibits T-cell proliferation by depleting the essential lymphocyte proliferation cofactor tryptophan . Other potentially important immunosuppressive actions of MSCs include suppression of B-lymphocyte proliferation and antibody production, inhibition of dendritic cell activation and potentially the induction of regulatory T cells . These mechanisms are summarized in Fig. 9.2 .

Only gold members can continue reading. Log In or Register to continue

Share this:

• Click to share on Twitter (Opens in new window)
• Click to share on Facebook (Opens in new window)

Related posts:

Mast Cells in Kidney Regeneration Use of Genetic Mouse Models to Study Kidney Regeneration Very Small Embryonic-like Stem Cells and Their Potential Relevance for Kidney Homeostasis Regeneration and Aging: Regulation by Sirtuins and the NAD +Salvage Pathway Potential Risks of Stem Cell Therapies Tissue Engineering in Urology

Stay updated, free articles. Join our Telegram channel

Join