Mesenchymal stem cells ameliorate diabetic glomerular fibrosis in vivo and in vitro by inhibiting TGF-β signalling via secretion of bone morphogenetic protein 7

Lv, Shunzeng; Liu, Gang; Sun, Aili; Wang, Jianping; Cheng, Jing; Wang, Weiwei; Liu, Xiangchun; Nie, Huibin; Guan, Guangju

doi:10.1177/1479164114531300

Cited by 62 publications

(45 citation statements)

References 30 publications

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“…Thus, they do not really differentiate into neuronal-like cells (13). Cellular fusion mechanism refers to when BMSCs and nerve cells are cultured together, and thus two cells become fused, resulting in gene fusion and the regulation of the gene expression of BMSCs, making the morphology and functions similar to those of nerve cells (14). In this study, the overexpression of miR-214 suppressed osteogenic differentiation and the downregulation of miR-214 activated thez osteogenic differentiation of BMSCs.…”

Section: Discussionmentioning

confidence: 99%

miR-214 suppresses the osteogenic differentiation of bone marrow-derived mesenchymal stem cells and these effects are mediated through the inhibition of the JNK and p38 pathways

Guo

Gao

et al. 2016

International Journal of Molecular Medicine

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In this study, we sought to investigate the expression of microRNA (miR)-214 on the osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) and explore the possible underlying mechanisms. We found that the overexpression of miR-214 effectively promoted the adipocyte differentiation of BMSCs in vitro, reduced alkaline phosphatase (ALP) activity and the gene expression of collagen type I (Col I), osteocalcin (OCN) and osteopontin (OPN) in the BMSCs. We further found that the overexpression of miR-214 suppressed the protein expression of fibroblast growth factor (FGF), phosphorylated c-Jun N-terminal kinase (p-JNK) and phosphorylated p38 (p-p38) in the BMSCs. The downregulation of miR-214 promoted the osteogenic differentiation of BMSCs, and increased ALP activity and Col I, OCN and OPN gene expression in the BMSCs. It also increased FGF p-JNK and p-p38 protein expression in the BMSCs. The use of JNK inhibitor (SP600125) enhanced the inhibitory effects of miR-214 overexpression on osteogenic differentiation, ALP activity, and Col I, OCN and OPN gene expression in the BMSCs. Lastly, the use of p38 inhibitor (SB202190) also enhanced the inhibitory effects of miR-214 overexpression on ALP activity, and Col I, OCN and OPN gene expression in the BMSCs. These results provide a mechanism responsible for the suppressive effects of miR-214 on the osteogenic differentiation of BMSCs involving the inhibition of the JNK and p38 pathways.

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Section: Discussionmentioning

confidence: 99%

miR-214 suppresses the osteogenic differentiation of bone marrow-derived mesenchymal stem cells and these effects are mediated through the inhibition of the JNK and p38 pathways

Guo

Gao

et al. 2016

International Journal of Molecular Medicine

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“…9 MSC have been reported to suppress some of the underlying inflammatory responses and oxidative stress associated with fibrosis, improve regulation of matrix deposition and remodeling, and inhibit the TGF-b pathway. [9][10][11][12][13][14] Encouraging findings have shown reduced albuminuria, collagen IV deposition, and loss of peritubular capillaries, but MSC alone could not completely reverse or restore function, despite their abilities to facilitate endothelial and epithelial proliferation. 15,16 One possible explanation for the diminished responses to MSC in chronic kidney disease may be the limited amount of energy available to the cell during ongoing cell injury, a state that leads to a rapid depletion of cytoplasmic ATP.…”

Section: Introductionmentioning

confidence: 96%

Mesenchymal Stem Cells Synergize with 635, 532, and 405 nm Laser Wavelengths in Renal Fibrosis: A Pilot Study

O'Connor

Patil

et al. 2016

Photomedicine and Laser Surgery

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“…Further studies are needed to confirm if long-term LC removal could lead to complete renal recovery, to decipher the involved mechanisms and to test therapeutic strategies that could accelerate this process. In this latter view, it seems that therapy based on mesenchymal stem cells could be a valuable approach, as demonstrated in rodent models of glomerulopathies (49,50) or more recently in ex vivo models of monoclonal LC-induced glomerular damages (51). Our model also enabled us to analyse the intrinsic toxicity of pathogenic monoclonal LC for plasma cells.…”

Section: Discussionmentioning

confidence: 88%

Glomerulosclerosis and kidney failure in a mouse model of monoclonal immunoglobulin light-chain deposition disease

Bender

Ayala

Bonaud

et al. 2019

Preprint

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Light chain deposition disease (LCDD) is a rare disorder characterized by glomerular and peritubular amorphous deposits of a monoclonal immunoglobulin (Ig) light chain (LC), leading to nodular glomerulosclerosis and nephrotic syndrome. We developed a transgenic model using site-directed insertion of the variable domain of a pathogenic human LC gene into the mouse Ig kappa locus, ensuring its production by all plasma cells. High free LC levels were achieved after backcrossing with mice presenting increased plasma cell differentiation and no Ig heavy chain (HC) production. Our mouse model recapitulates the characteristic features of LCDD, including progressive glomerulosclerosis, nephrotic-range proteinuria and finally, kidney failure. The variable domain of the LC bears alone the structural properties involved in its pathogenicity. RNA sequencing conducted on plasma cells demonstrated that LCDD LC induces endoplasmic reticulum stress, likely accounting for the high efficiency of proteasome inhibitor-based therapy. Accordingly, reduction of circulating pathogenic LC was efficiently achieved and not only preserved renal function, but partially reversed kidney lesions. Finally, transcriptome analysis of pre-sclerotic glomeruli revealed that proliferation and extracellular matrix remodelling represented the first steps of glomerulosclerosis, paving the way for future therapeutic strategies in LCDD and other kidney diseases featuring diffuse glomerulosclerosis, particularly diabetic nephropathy. Introduction : Monoclonal gammopathies of renal significance (MGRS) are characterized by renal lesions due to monoclonal immunoglobulins produced by a non-malignant B or plasma cell clone (1). Depending on the type and structural properties of the Ig, they comprise tubulopathies caused by LC accumulating in the proximal or distal tubules, or glomerulopathies, most frequently AL amyloidosis and Randall-type monoclonal Ig deposition disease (MIDD) (2). MIDD are characterized by linear amorphous deposits of a monoclonal LC (LCDD) or a truncated HC (HCDD) along the tubular and glomerular basement membranes (BMs), around arteriolar myocytes and in the mesangium, eventually leading to diabetic-like nodular glomerulosclerosis. Clinical manifestations include glomerular proteinuria with progressive kidney failure (3-5). In LCDD, the most frequent form of MIDD, involved LCs are mostly of the kappa isotype, with a striking overrepresentation of the Vk4 variable domain characterized by a long CDR1. Other peculiarities of LCDD LCs are due to somatic hypermutations and include polar to hydrophobic amino-acids replacements, small truncations or abnormal glycosylations (3, 4, 6-10). Moreover, LCDD LCs are characterized by the constant high isoelectric point (pI) of their V domain compared to LCs involved in AL amyloidosis (11).This feature was also confirmed in HCDD and could account for the high avidity of positively charged LCs for anionic heparan sulfates of basement membranes (5). However, little is known about the pathogenic mechanisms i...

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Mesenchymal stem cells ameliorate diabetic glomerular fibrosis in vivo and in vitro by inhibiting TGF-β signalling via secretion of bone morphogenetic protein 7

Cited by 62 publications

References 30 publications

miR-214 suppresses the osteogenic differentiation of bone marrow-derived mesenchymal stem cells and these effects are mediated through the inhibition of the JNK and p38 pathways

miR-214 suppresses the osteogenic differentiation of bone marrow-derived mesenchymal stem cells and these effects are mediated through the inhibition of the JNK and p38 pathways

Mesenchymal Stem Cells Synergize with 635, 532, and 405 nm Laser Wavelengths in Renal Fibrosis: A Pilot Study

Glomerulosclerosis and kidney failure in a mouse model of monoclonal immunoglobulin light-chain deposition disease

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