MSCs derived from ADSC-reprogrammed iPSCs exhibit enhanced therapeutic potential for treating skin fibrosis

Localized scleroderma (LoS) is a fibrotic skin disorder characterized by excessive collagen deposition, leading to functional and cosmetic impairments. Mesenchymal stromal cells (MSCs) offer therapeutic potential through immunomodulation and tissue repair, but their clinical use is limited by donor variability and replicative senescence. Induced pluripotent stem cell (iPSC)-derived MSCs (iMSCs) present a promising alternative owing to their scalable production and rejuvenated phenotype.

We generated adipose-derived iMSCs (AD-iMSCs) from reprogrammed adipose-derived stem cells (ADSCs) and compared their therapeutic efficacy to primary ADSCs in vitro and in vivo. Functional assays including transcriptomic profiling, conditioned medium (CM) effects on fibrosis markers (α-SMA, TGF-β/Smad), and angiogenesis were conducted. A bleomycin-induced murine LoS model was employed to assess AD-iMSC engraftment, collagen deposition, and microvascularization.

AD-iMSCs exhibited rejuvenated-like phenotype, with reduced senescence markers and enhanced proliferative capacity. AD-iMSC-derived conditioned medium (AD-iMSCs-CM) outperformed ADSC-derived conditioned medium (ADSC-CM) in promoting angiogenesis in vitro. In vivo, AD-iMSCs demonstrated superior persistence and therapeutic efficacy, notably decreasing dermal thickness and collagen density while promoting vascularization. Mechanistically, AD-iMSCs more effectively suppressed the TGF-β/Smad2/3 signaling and extracellular matrix (ECM) remodeling pathways compared to ADSCs.

In conclusion, our findings provide a robust preliminary proof-of-concept demonstrating that iPSC-mediated reprogramming yields iMSCs with rejuvenated-like phenotype and a potent anti-fibrotic secretome. These data offer a valuable molecular and functional rationale for the prospective development of iMSC-based platforms to circumvent the expansion limitations and donor variability inherent to primary MSC therapies for fibrotic skin disorders.