Mesenchymal stem cells reversibly de-differentiate myofibroblasts to fibroblast-like cells by inhibiting the TGF-β-SMAD2/3 pathway

Molecular Medicine, Journal Year: 2023, Volume and Issue: 29(1)

Published: April 25, 2023

Abstract Background Myofibroblasts (MFB), one of the major effectors pathologic fibrosis, mainly derived from activation fibroblast to myofibroblast transition (FMT). Although MFBs were historically considered terminally differentiated cells, their potential for de-differentiation was recently recognized and implied with therapeutic value in treating fibrotic diseases, instance, idiopathic pulmonary fibrosis (IPF) post allogeneic hematopoietic stem cell transplantation bronchiolitis obliterans (BO). During past decade, several methods reported block or reverse MFB differentiation, among which mesenchymal cells (MSC) have demonstrated but undetermined values. However, MSC-mediated regulation FMT underlying mechanisms remained largely undefined. Method By identifying TGF-β1 hypertension as pivotal landmark during pro-fibrotic FMT, TGF-β1-induced MSC co-culture models established utilized investigate regulations by on vitro. Methods including RNA sequencing (RNA-seq), Western blot, qPCR flow cytometry used. Result Our data revealed that readily induced invasive signatures identified tissues initiated differentiation normal FB. reversibly de-differentiated into a group FB-like selectively inhibiting TGF-β-SMAD2/3 signaling. Importantly, these proliferation-boosted sensitive could be re-induced MFB. Conclusion findings highlighted reversibility through signaling, may explain MSC's inconsistent clinical efficacies BO other diseases. These are still further deteriorate phenotypes unless microenvironment is corrected.

Language: Английский

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The role of immunosuppressive myofibroblasts in the aging process and age-related diseases

Journal of Molecular Medicine, Journal Year: 2023, Volume and Issue: 101(10), P. 1169 - 1189

Published: Aug. 22, 2023

Abstract Tissue-resident fibroblasts are mesenchymal cells which control the structural integrity of extracellular matrix (ECM). Fibroblasts possess a remarkable plasticity to allow them adapt changes in microenvironment and thus maintain tissue homeostasis. Several stresses, also those associated with aging process, convert quiescent into myofibroblasts not only display fibrogenic properties but act as immune regulators cooperating both tissue-resident recruited affected tissues. TGF-β cytokine reactive oxygen species (ROS) major inducers myofibroblast differentiation pathological conditions either from or via transdifferentiation certain other cell types, e.g., macrophages, adipocytes, pericytes, endothelial cells. Intriguingly, ROS important signaling mediators between immunosuppressive cells, such MDSCs, Tregs, M2 macrophages. It seems that states, able interact network. There is clear evidence low-grade chronic inflammatory state tissues counteracted by activation compensatory immunosuppression. Interestingly, common enhancers oxidative stress, loss DNA integrity, insults, myofibroblasts, whereas anti-aging treatments metformin rapamycin suppress prevent age-related fibrosis. I will examine reciprocal interactions within harmful stresses enhances activity network promotes fibrosis degeneration elderly individuals.

Language: Английский

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Novel prospects for scarless wound healing: The roles of myofibroblasts and adipocytes

Journal of Cellular and Molecular Medicine, Journal Year: 2022, Volume and Issue: 26(20), P. 5113 - 5121

Published: Sept. 15, 2022

Abstract Disturbances or defects in the process of wound repair can disrupt delicate balance cells and molecules necessary for complete healing, thus leading to chronic wounds fibrotic scars. Myofibroblasts are one most important involved scars, reprogramming provides a potential avenue increase myofibroblast clearance. Although myofibroblasts have long been recognized as terminally differentiated cells, recent studies shown that capacity be reprogrammed into adipocytes. This review intends summarize We will discuss lineage tracing, well known mechanisms underlying adipocyte regeneration from myofibroblasts. In addition, we investigated different changes gene expression, transcriptional regulators, signalling pathways epigenetic regulators during skin healing. future, healing better understood appreciated, which may provide new ideas treatment scarless

Language: Английский

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Perspectives of PDE inhibitor on treating idiopathic pulmonary fibrosis

Frontiers in Pharmacology, Journal Year: 2023, Volume and Issue: 14

Published: Feb. 14, 2023

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease (ILD) without an identifiable cause. If not treated after diagnosis, the average life expectancy 3–5 years. Currently approved drugs for treatment of IPF are Pirfenidone and Nintedanib, as antifibrotic drugs, which can reduce decline rate forced vital capacity (FVC) risk acute exacerbation IPF. However these relieve symptoms associated with IPF, nor improve overall survival patients. We need to develop new, safe effective treat fibrosis. Previous studies have shown that cyclic nucleotides participate in pathway play essential role process Phosphodiesterase (PDEs) involved nucleotide metabolism, so PDE inhibitors candidates This paper reviews research progress related fibrosis, provide ideas development anti-pulmonary drugs.

Language: Английский

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Investigational gene expression inhibitors for the treatment of idiopathic pulmonary fibrosis

Expert Opinion on Investigational Drugs, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 20

Published: Feb. 7, 2025

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing interstitial lung disease of unknown cause that occurs primarily in older adults and associated with poor quality life substantial healthcare utilization. IPF has dismal prognosis. Indeed, first-line therapy, which includes nintedanib pirfenidone, does not stop progression often tolerability issues. Therefore, there remains high medical need for more efficacious better tolerated treatments. Gene therapy relatively unexplored field research the potential to mitigate range profibrotic pathways by introducing genetic material into cells. Here, we summarize critically discuss publications have explored safety efficacy gene experimentally-induced animals, as clinical studies humans been published yet. The application requires further investigation address several technical biological hurdles, improve vectors' design, drug delivery, target selection, off-target effects develop markers penetration Long-term data are needed bring one step closer practice.

Language: Английский

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