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Background: <p>Systemic sclerosis (SSc) is characterized by progressive dermal fibrosis and microvascular dysfunction, and no approved therapy reliably reverses established skin fibrosis or durably restores microvascular perfusion. Adipose-derived stem cells (ASCs) possess anti-fibrotic, immunomodulatory, and vascular-related parameters properties, but their therapeutic impact in a strictly therapeutic (rather than preventive) SSc-like setting remains incompletely defined.</p> Methods: <p>Bleomycin-induced systemic sclerosis model was induced in male C57BL/6 mice by daily subcutaneous bleomycin injections (100&#xa0;μg) into dorsal skin for 28&#xa0;days. On day 14, mice received a single intralesional injection of ASCs (1 × 10<sup>5</sup> cells) or vehicle. At day 28, cutaneous perfusion was measured by laser Doppler perfusion imaging, and dorsal skin was analyzed by histology, hydroxyproline assay, RT-qPCR, and immunohistochemistry for CD34, α-SMA, and TNF-α. To support mechanistic interpretation, TGF-β1–stimulated dermal fibroblasts were co-cultured with ASCs and fibrosis-related gene expression was assessed.</p> Results: <p>Intralesional ASC administration significantly attenuated bleomycin-induced dermal fibrosis, reducing dermal thickness (244.0–163.5&#xa0;μm) and collagen area fraction (87.2–62.8%). Hydroxyproline content decreased from 0.187 to 0.121&#xa0;μg/mg tissue. ASC treatment also suppressed profibrotic and inflammatory transcripts (α-SMA ~ 3.99-fold, TGF-β1 ~ 6.07-fold, TNF-α ~ 7.48-fold, IL-6 ~ 2.36-fold vs. BLM + PBS) and increased vascular responses transcripts (VEGF ~ 2.65-fold, CD34 ~ 1.28-fold vs. BLM + PBS). ASC co-culture suppressed profibrotic activation of TGF-β1–stimulated fibroblasts, reducing profibrotic expression (α-SMA ~ 2.5-fold, TGF-β1 ~ 3.5 -fold, and COL1A1 ~ 2.7-fold).</p> Conclusions: <p>A single intralesional ASC injection alleviated established bleomycin-induced dermal fibrosis and was associated with vascular-related changes in fibrotic tissue. These effects may involve paracrine-mediated suppression of TGF-β1–driven fibroblast activation, supporting ASCs as a promising regenerative strategy for systemic sclerosis skin disease.</p>

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Intralesional Adipose-Derived Stem Cells Reverse Established Dermal Fibrosis and Modulate Angiogenesis-Related Readouts in a Murine Systemic Sclerosis Model

  • 期刊论文

  • 发表日期：

    2026年4月25日

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  • Eunji Lee,
  • Yeon Hee Ryu,
  • Su Jin Lee,
  • So Hyun Kwon,
  • Suk-Ho Moon

摘要

Background:

Systemic sclerosis (SSc) is characterized by progressive dermal fibrosis and microvascular dysfunction, and no approved therapy reliably reverses established skin fibrosis or durably restores microvascular perfusion. Adipose-derived stem cells (ASCs) possess anti-fibrotic, immunomodulatory, and vascular-related parameters properties, but their therapeutic impact in a strictly therapeutic (rather than preventive) SSc-like setting remains incompletely defined.

Methods:

Bleomycin-induced systemic sclerosis model was induced in male C57BL/6 mice by daily subcutaneous bleomycin injections (100 μg) into dorsal skin for 28 days. On day 14, mice received a single intralesional injection of ASCs (1 × 105 cells) or vehicle. At day 28, cutaneous perfusion was measured by laser Doppler perfusion imaging, and dorsal skin was analyzed by histology, hydroxyproline assay, RT-qPCR, and immunohistochemistry for CD34, α-SMA, and TNF-α. To support mechanistic interpretation, TGF-β1–stimulated dermal fibroblasts were co-cultured with ASCs and fibrosis-related gene expression was assessed.

Results:

Intralesional ASC administration significantly attenuated bleomycin-induced dermal fibrosis, reducing dermal thickness (244.0–163.5 μm) and collagen area fraction (87.2–62.8%). Hydroxyproline content decreased from 0.187 to 0.121 μg/mg tissue. ASC treatment also suppressed profibrotic and inflammatory transcripts (α-SMA ~ 3.99-fold, TGF-β1 ~ 6.07-fold, TNF-α ~ 7.48-fold, IL-6 ~ 2.36-fold vs. BLM + PBS) and increased vascular responses transcripts (VEGF ~ 2.65-fold, CD34 ~ 1.28-fold vs. BLM + PBS). ASC co-culture suppressed profibrotic activation of TGF-β1–stimulated fibroblasts, reducing profibrotic expression (α-SMA ~ 2.5-fold, TGF-β1 ~ 3.5 -fold, and COL1A1 ~ 2.7-fold).

Conclusions:

A single intralesional ASC injection alleviated established bleomycin-induced dermal fibrosis and was associated with vascular-related changes in fibrotic tissue. These effects may involve paracrine-mediated suppression of TGF-β1–driven fibroblast activation, supporting ASCs as a promising regenerative strategy for systemic sclerosis skin disease.