Multipotent mesenchymal stem cells reduce interstitial fibrosis but do not delay progression of chronic kidney disease in collagen4A3-deficient mice

Abstract

Multipotent mesenchymal stem or stromal cells (MSC) have shown to improve outcome of acute renal injury models, but whether MSC can delay renal failure in chronic kidney disease is not known. We injected primary MSC or saline into mice that lack the alpha3-chain of type IV collagen (COL4A3), a model of chronic kidney disease with close similarities to human Alport disease. Weekly injections of MSC from week 6 to 10 of life prevented the loss of peritubular capillaries and reduced markers of renal fibrosis, that is, interstitial volume, numbers of smooth muscle actin-positive interstitial cells, and interstitial collagen deposits as compared to saline-injected COL4A3-deficient mice. However, renal function, that is, blood urea nitrogen, creatinine levels, proteinuria as well as survival of COL4A3-deficient mice were not affected by MSC injections. Although MSC were found to localize to kidneys of COL4A3-deficient mice after injection, differentiation into renal cells was not detected. However, MSC expressed growth factors, that is, vascular endothelial growth factor (VEGF) and bone morphogenetic protein-7 under basal culture conditions. In fact, VEGF mRNA levels were increased in kidneys of MSC-injected COL4A3-deficient mice and MSC supernatants enhance endothelial cell proliferation in vitro. Thus, weekly injections with MSC prevent loss of peritubular capillaries possibly owing to local production of growth factors rather than by differentiation into renal cells. The maintenance of interstitial vasculature is associated with less interstitial fibrosis but, is insufficient to delay renal failure and survival of COL4A3-deficient mice.

Mesenchymal Stem Cells Attenuate Renal Fibrosis Through Immune Modulation and Remodeling Properties in a Rat Remnant Kidney Model

“…Herein, the animals treated with MSCs showed increased expression of HGF and HO-1. HGF binds to Met, a transmembrane receptor belonging to the tyrosine kinase superfamily that inhibits the progression of fibrosis in several models, such as remnant kidney [53], unilateral ureteral obstruction [54,55], and diabetic nephropathy [56,57]. HGF expression in MSC-treated animals most likely correlates with their own secretion, as previously reported [26].…”

Stem cell options for kidney disease

“…Furthermore, ex vivo manipulation of macrophages using specific cytokines confirmed that classically activated, M1 macrophages worsen chronic inflammatory adriamycin nephropathy, whereas alternatively activated M2 macrophages reduce histological disruption and functional injury [36]. Of note, in the heart Camargo et al [37] have [39] Glycerol-induced ARF (mouse) MSCs Enhanced tubular proliferation [68] IR (rat) Papilla LRCs Proliferation and incorporation [149] IR (mouse) Bone marrow No functional improvement, intrarenal cells are the main source of repopulating cell during repair [22] Folic acid-induced acute tubular injury (mouse) Bone marrow Intrinsic tubular cell proliferation accounts for repair after damage [150] Folic acid-induced acute tubular injury (mouse) Bone marrow 10% incorporation in tubules and G-CSF doubles this rate [151] IR (rat) MSCs Improved renal function and less injury [152] Cisplatin-induced renal failure (mouse) MSCs Accelerated tubular proliferation [153] UUO (mouse) Bone marrow macrophages Reduced renal fibrosis [41] IR (rat) MSCs Improved renal function, increased proliferation and decreased apoptosis [84] IR (rat) rKS56 (S3 segment outgrowth) Replace tubular and improve function [80] Glycerol-induced tubulonecrosis (mouse) Human CD133 + cells Homing and tubular integration [66] UUO (rat) Label-retaining cells (LRC) Proliferates, migrates and transdifferentiates into fibroblast-like cells [27] Cisplatin-induced renal failure (mouse) G-CSF ± M-CSF Improvement in renal function and prevention of renal tubular injury [154] Anti-Thy1.1 GN (rat) MSCs Increased glomerular proliferation and reduction in proteinuria [53] Col4α3 deficiency (mouse) MSCs Prevented loss of peritubular capillaries and reduced fibrosis but no increase in function or survival [24] Col4α3 deficiency (mouse) Bone marrow Partial restoration of expression of the type IV collagen α3 chain, improved histology and function [25] Col4α3 deficiency (mouse) MSCs Improved function and glomerular scarring and interstitial fibrosis reduced [155] UUO (mouse) BM Instertitial BM-derived cells do not contribute significantly to collagen synthesis after damage [74] Adriamycin-nephropathy (mouse) Renal side population Functional amprovement but very low rate of engraftment. [78] IR (rat) Multipotent renal progenitor cells In vivo epithelial differentiation, no difference on renal function [67] Cultured met...…”

“…While animal studies involving models of IR or chemically-induced AKI have shown consistent improvement after MSC delivery, their effectiveness in chronic damage models is less clear [53]. Some studies have shown improvement after MSC delivery in a model of glomerulonephropathy [54] and no evidence of a long-term fibrotic response 3 months after delivery of MSCs to animals with severe AKI [44].…”

“…Other studies have shown that in models of glomerular injury MSCs have no beneficial effect. Ninichuk et al [53], using the murine genetic model of Alport syndrome, delivered isolated MSCs and concluded that while MSCs did reduce interstitial fibrosis, they failed to prevent progression. Despite these concerns and variable results, the first Phase 1 trial of MSCs in AKI is scheduled to begin shortly and will involve cardiac patients at high risk of developing AKI [56].…”

Adult bone marrow–derived stem cells for organ regeneration and repair

“…Another concern, besides tumor formation, is development of fibrosis (Iwano et al, 2002;Russo et al, 2006), since MSCs are fibroblast-like cells and are stimulated by TGF-␤, a factor that has been shown to be the major factor in the development of tissue fibrosis. Animal models of BMDC treatment have actually shown that these cell preparations are protective of tissue fibrosis rather than profibrotic (Ortiz et al, 2003;Zhao et al, 2005;Ninichuk et al, 2006), rendering the potential contribution of MSCs to fibrosis insignificant.…”