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Mesenchymal stem cells reversibly dedifferentiate myofibroblasts to fibroblast-like cells by down-regulating the TGF-β-SMAD2/3 pathway

ABSTRACT: Bronchiolitis obliterans (BO) is a pulmonary chronic graft-versus-host disease (cGVHD), which is a noninfectious, irreversible, and poor prognostic complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Fibroblast-myofibroblast transition (FMT)-derived myofibroblasts (MFB) are the main effector cells involved in the development of BO. Through multiple regulations, the anti-fibrotic potential of mesenchymal stem cells (MSC) has been widely studied and was implied with potential clinical value. However, the MSC-mediated regulation of FMT and underlying mechanisms remained largely undefined. By identifying TGF-β1 hypertension as the pivotal landmark during the profibrotic FMT, TGF-β1-induced MFB and uMSC co-culture models were established and utilized to investigate regulations by uMSC on FMT in vitro. Methods including RNA sequencing (RNA-seq), Western blot, qPCR and flow cytometry were used. Our results revealed that uMSC reversibly dedifferentiated MFB into a group of FB-like cells by modulating the TGF-β-SMAD2/3 signaling. Importantly, these proliferation-boosted FB-like cells remained sensitive to TGF-β1 and could be re-induced into MFB. Our findings highlighted the reversibility of uMSC-mediated inhibitions on FMT through TGF-β-SMAD2/3 signaling, which may explain MSC's inconsistent clinical efficacies in treating BO and other fibrotic diseases. These dedifferentiated FB-like cells are still sensitive to TGF-β1 and may further deteriorate MFB phenotypes unless the profibrotic environment is corrected.

ORGANISM(S): Homo sapiens

PROVIDER: GSE225159 | GEO | 2023/02/18

REPOSITORIES: GEO

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Project description:We aimed to identify miRNA biomarkers of renal injury in kidney biopsies from patients with lupus nephritis. MiRNA profiles of 8 patients were analyzed for correlation with various clinical features including Progression, Activity, Chronicity, and Time to Kidney Failure. MicroRNAs (miRs) are promising biomarkers and are involved in pathogenesis of kidney diseases. We aimed to identify miR biomarkers of renal injury in kidney biopsies from patients with lupus nephritis and study their potential role in renal fibrosis. miR-150 was significantly increased in kidneys with high chronicity compared to low chronicity and it correlated positively with chronicity index scores and renal collagen I expression. In kidneys with high chronicity, miR-150 was found predominantly in proximal tubular cells (PTCs) and was moderately expressed in podocytes and to lesser degree in mesangial cells (MCs). We hypothesized that miR-150 increases fibrosis by downregulating a negative regulator of profibrotic proteins. Suppressor of cytokine signaling1 (SOCS1) is a predicted target of miR-150 and has shown antifibrotic role. After confirming that SOCS1 is a direct target of miR-150, we showed that transfection of a miR-150 analog downregulated SOCS1 protein and upregulated the profibrotic proteins fibronectin, collagen I, collagen III, and TGF-β1 in both primary normal human renal PTCs and MCs. A similar effect was seen when using a SOCS1 siRNA to confirm that the effect of miR-150 on profibrotic proteins is mediated through SOCS1. Stimulation with TGF-β1 induced miR-150 increase in PTCs and human podocytes but not MCs. These results suggest that miR-150 might be a useful quantitative renal biomarker of kidney injury in lupus nephritis and that miR-150, which might be partially induced by TGF-β1, plays an important role in renal fibrosis by increasing profibrotic molecules through downregulation of SOCS1. FFPE kidney specimens (n=25) including baseline and repeated needle renal biopsies were from 14 patients with LN enrolled in IRB-approved protocols at the NIDDK between 1976 and 1999. The specimens were divided in two groups based on histological chronicity index (CI). CI ≥ 4 were categorized as having high degree of chronicity of chronic kidney injury. 18 kidneys from 8 patients including high CI (n=9) and low CI (n=9) were used for miR profiling by Affymetrix microRNA microarrays.

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Mesenchymal stem cells reversibly dedifferentiate myofibroblasts to fibroblast-like cells by down-regulating the TGF-β-SMAD2/3 pathway

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