Bone-marrow-derived stem cells repair basement membrane collagen defects and reverse genetic kidney disease

Abstract

Type IV collagen is a predominant component of basement membranes, and glomeruli of a kidney filter Ϸ70 -90 liters of plasma every day through a specialized glomerular basement membrane (GBM). In Alport syndrome, a progressive disease primarily affecting kidneys, mutations in GBM-associated type IV collagen genes (COL4A3, COL4A4, or COL4A5) lead to basement membrane structural defects, proteinuria, renal failure, and an absence of all three GBM collagen triple helical chains because of obligatory posttranslational assembly requirements. Here, we demonstrate that transplantation of wild-type bone marrow (BM) into irradiated COL4A3 ؊/؊ mice results in a possible recruitment of BM-derived progenitor cells as epithelial cells (podocytes) and mesangial cells within the damaged glomerulus, leading to a partial restoration of expression of the type IV collagen ␣3 chain with concomitant emergence of ␣4 and ␣5 chain expression, improved glomerular architecture associated with a significant reduction in proteinuria, and improvement in overall kidney histology compared with untreated COL4A3 ؊/؊ mice or irradiated COL4A3 ؊/؊ mice with BM from adult COL4A3 ؊/؊ mice. The ␣3(IV) collagen produced by BM-derived podocytes integrates into the GBM and associates with other ␣-chains to form type IV collagen triple helical networks. This study demonstrates that BM-derived stem cells can offer a viable strategy for repairing basement membrane defects and conferring therapeutic benefit for patients with Alport syndrome.Alport syndrome ͉ bone marrow transplantation ͉ glomerular basement membrane ͉ type IV collogen ␣3 chain ͉ glomeruli

Irradiation Prolongs Survival of Alport Mice

“…Two recent article reported evidence for the GBM expression of type IV collagen ␣3 chains and improved renal function after wild-type BMT to the Col4a3-deficient AS mice 10,11 ; however, Sugimoto et al 10 did not present any data of KO to KO BMT mice, and those of Prodromidi et al 11 were also limited (the study group was composed of three mice). Those studies differ from this one in regard to the time of transplantation and the strain.…”

“…10,11 Both groups showed some improvement in renal injury on the basis of the laboratory data and histology; however, so far, no report has addressed the survival time of these mice, which is essential to judge the effectiveness of bone marrow transplantation (BMT). 12 Therefore, the short-term and long-term effects on BMT were analyzed in our study using larger sample sizes.…”

Stem cell options for kidney disease

“…Nevertheless, BM transplantation can improve renal function. Whole BM transplantation has been reported to be able to improve renal function and reduce histological damage in the collagen4α3 defective model of Alport syndrome [24,25]. These authors reported that BM-derived cells transdifferentiated into podocytes and mesangial cells, accompanied by re-expression of the defective collagen chains and improved renal histology and function.…”

“…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...…”

“…There have been very few studies performed using animal models of chronic renal diseases, despite the plethora of experimental and genetic murine models of glomerulosclerosis or glomerulonephritis available. The utility of MSCs has been assessed in collagen4α3 [25,24] and 1α2 mutant mice [143] and streptozocin-induced type 1 diabetes [144,145], but no studies of stem cells in the db/db model of diabetic nephropathy have been reported and the only study in which stem cells have been examined in a model of end stage renal disease utilized human fetal kidney cells [146]. The diversity of pathology present in CKD may also mean that no one cellular therapy will be applicable to all conditions.…”