Chemical direct conversion of human fibroblasts to mesenchymal stem cells that can alleviate inflammation in vivo

TL;DR

Scientists converted human skin cells into stem cells that reduce inflammation in mice, offering a new approach for treating inflammatory diseases.

Contribution

A chemical method to directly convert fibroblasts into functional mesenchymal stem cells with anti-inflammatory properties.

Findings

A combination of three inhibitors converted fibroblasts into MSC-like cells with multilineage differentiation potential.

The converted cells reduced inflammation in mouse models of lung injury and arthritis.

Exosomes from the converted cells promoted anti-inflammatory macrophage polarization.

Abstract

Mesenchymal stem cell (MSC) transplantation may significantly benefit patients with some inflammatory diseases. However, invasive procedures are required to collect autologous MSCs from patients, while in vitro expansion of MSCs may spoil their stemness. In this study, we aimed to induce MSC-like phenotypes in human dermal fibroblasts (HDFs).

HDFs were cultured with some chemical compounds. The resultant cells were examined for their gene expression and multi-differentiation abilities in vitro. Anti-inflammatory functions in vivo were tested using two types of disease models in mice. Exosomes derived from the cells were also characterized.

A combination of a TGF-β receptor inhibitor, a ROCK inhibitor, and an ATM inhibitor provoked HDFs to strongly express MSC markers. The chemical compound-driven directly converted MSCs (cdMSCs) had multilineage differentiation potentials to osteogenic, chondrogenic, and adipogenic lineages in vitro. The genes related to TGF-β, MAPK, Hedgehog and WNT signaling pathways were remarkably changed in expression levels, while CpG DNA methylation statuses were also altered, during the cell type transition. The cdMSCs ameliorated both acute and chronic inflammatory diseases after transplantation into murine models of LPS-induced lung injury and autoimmune arthritis. The cdMSCs secreted exosomes that promoted polarization of M0 macrophages to M2 phenotype while suppressing M1 macrophage induction in vitro.

The three compounds successfully converted HDFs into MSC-like cells with high anti-inflammatory activities, which would be useful in regenerative medicine for inflammatory disease.

The online version contains supplementary material available at 10.1186/s13287-025-04605-x.

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