Adipose-Derived Stem Cell Therapy Ameliorates Ionizing Irradiation Fibrosis via Hepatocyte Growth Factor-Mediated Transforming Growth Factor-β Downregulation and Recruitment of Bone Marrow Cells

Abstract

Radiation therapy to anatomic regions, including the head and neck, chest wall, and extremities, can produce radiation‐induced fibrosis (RIF). To elucidate the cellular and molecular mechanism(s) involved in RIF, female C57BL/6J mice were irradiated to the right flank to 35 Gy in single fraction using 6 Mv electrons. Radiation fibrosis was detected by day 14, was increased by day 28, and confirmed by Masson's trichrome histological staining for collagen. Biopsied tissue at day 14 showed an increase in expression of fibrosis‐related genes including transforming growth factor‐β (TGF‐β) and collagens 1–6. A single adipose‐derived stem cell (ASC) injection on day 28 at the irradiated site decreased by day 40: epithelial thickness, collagen deposition, and significantly improved limb excursion compared with irradiated controls. Noncontact transwell coculture of ASCs above a monolayer of irradiated human foreskin fibroblasts downregulated fibrosis‐related genes TGF‐β, connective tissue growth factor, interleukin‐1, NF‐kB, tumor necrosis factor, and collagens 1–6. Hepatocyte growth factor (HGF) secreted by ASCs was identified as a novel mechanism by which ASCs exert antifibrotic effects by downregulating fibrotic gene expression in irradiated cells and recruiting bone marrow cells to the irradiated site. In conclusion, these data indicate a mechanistic role of HGF secreted by ASCs in reducing RIF. Stem Cells 2019;37:791–802

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“…To explore the potential of fat grafting as a therapeutic approach to the limb contracture and lost functionality induced by the progressive and pathological soft tissue fibrosis stimulated by radiation therapy, researchers led by Derrick C. Wan (Stanford University, Stanford, California) adapted a previously established and well‐understood nude mouse model . As described in their recent article published in STEM CELLS , Borrelli et al employed this model to evaluate two different experimental approaches administered at four weeks post‐irradiation‐fat grafting and also the grafting of fat enriched with stromal vascular cells, given the improved outcomes observed using fat enriched with adipose‐derived MSCs .…”

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“…Cell therapies for RIF have included MSC‐ and endothelial cell‐based approaches ; however, recent results have suggested that the application of ASCs or autologous fat tissue may represent a potentially effective means to treat fibrosis . In a recent Stem Cells article, researchers led by J. Peter Rubin (University of Pittsburgh, Pennsylvania, USA) sought to confirm the potential of ASCs as a therapy for RIF in vivo and explore the mechanisms controlling the therapeutic effect . Ejaz et al first studied a mouse model of RIF, which involved a single focused dose of radiation to the mouse hind limb with the loss of limb movement acting as a functional readout for fibrotic development.…”

“…In our second Featured Article published in Stem Cells Translational Medicine this month, Imafuku et al report that the allogeneic transplantation of rat bone‐marrow MSC (BMSC) sheets onto the kidney surface of a rat renal ischemia‐reperfusion‐injury model prevents renal fibrosis via microvascular protection . In a Related Article published in Stem Cells , Ejaz et al established the ability of ASCs to improve limb movement and skin epithelial architecture in a mouse model of RIF and highlighted the essential role of secreted hepatocyte growth factor (HGF) .…”

Sphingosine‐1‐phosphate alleviates irradiation‐induced parotid injury in a miniature pig model

“…However, some patients with HNC who receive irradiation (IR) still suffer from long‐term salivary gland injury (Ghosh‐Laskar et al, ). Gene therapy (Gao et al, ; Hu et al, ), stem cell treatment (Ejaz, Epperly, Hou, Greenberger, & Rubin, ) and molecular medicine (Hu et al, ) have been used to alleviate tissue damage associated with IR, but these strategies do not fulfil the clinical demands. Therefore, new techniques and strategies must be employed for the treatment of IR‐induced oral tissue injury.…”