Mesenchymal stromal cells prevent bleomycin‐induced lung and skin fibrosis in aged mice and restore wound healing

Abstract

Fibrosis can develop in nearly any tissue leading to a wide range of chronic fibrotic diseases. However, current treatment options are limited. In this study, we utilized an established aged mouse model of bleomycin-induced lung fibrosis (BLM) to test our hypothesis that fibrosis may develop simultaneously in multiple organs by evaluating skin fibrosis and wound healing. Fibrosis was induced in lung in aged (18-22-month-old) C57BL/6 male mice by intratracheal BLM administration. Allogeneic adipose-derived mesenchymal stromal cells (ASCs) or saline were injected intravenously 24 hr after BLM administration. Full thickness 8-mm punch wounds were performed 7 days later to study potential systemic anti-fibrotic and wound healing effects of intravenously delivered ASCs. Mice developed lung and skin fibrosis as well as delayed wound closure. Moreover, we observed similar changes in the expression of known pro-fibrotic factors in both lung and skin wound tissue, including miR-199 and protein expression of its corresponding target, caveolin-1, as well as phosphorylation of protein kinase B. Importantly, ASC-treated mice exhibited attenuation of BLM-induced lung and skin fibrosis and accelerated wound healing, suggesting that ASCs may prime injured tissues and prevent end-organ fibrosis.

A Flowable Placental Formulation Prevents Bleomycin-Induced Dermal Fibrosis in Aged Mice

“…Furthermore, the placental ECM provides a reservoir of growth factors and signaling molecules that direct tissue healing and regeneration [ 10 ]. Hence, MSCs, amniotic membrane or amniotic-derived conditioned media, and umbilical tissue have been recommended as potential anti-fibrotic therapies [ 8 , 11 , 12 , 13 , 14 ]. The beneficial effects of the aforementioned anti-fibrotic therapies have been studied and proven in several organs, including the lungs [ 11 , 15 ], heart [ 16 ], kidney [ 17 ], liver [ 18 ], abdominal injury [ 14 ] and skin [ 11 , 19 ].…”

“…Hence, MSCs, amniotic membrane or amniotic-derived conditioned media, and umbilical tissue have been recommended as potential anti-fibrotic therapies [ 8 , 11 , 12 , 13 , 14 ]. The beneficial effects of the aforementioned anti-fibrotic therapies have been studied and proven in several organs, including the lungs [ 11 , 15 ], heart [ 16 ], kidney [ 17 ], liver [ 18 ], abdominal injury [ 14 ] and skin [ 11 , 19 ]. Therefore, the anti-inflammatory and anti-fibrotic properties of human placenta and umbilical tissue make both well-suited as therapeutic agents to prevent inflammation and fibrosis [ 14 , 20 , 21 , 22 , 23 ].…”

“…While the bleomycin model has been used extensively to study fibrosis, the majority of studies have been performed in either young mice or in adult mice [ 24 , 25 ]. Bleomycin-induced fibrosis studies carried out in aged mice would serve to confirm age as a crucial factor in the occurrence of fibrosis [ 11 ].…”

The effects of BMMSC treatment on lung degeneration in elderly macaques

“…Numerous studies have suggested that mesenchymal stem cells can repair lung injury and effectively treat acute and/or chronic lung diseases [9][10][11] . However, the majority of these studies have been performed on rodents, and very few studies on primates exist.…”

The effects of BMMSC treatment on lung degeneration in elderly macaques

“…Numerous studies have suggested that mesenchymal stem cells can repair lung injury and effectively treat acute and/or chronic lung diseases [8][9][10] . However, the majority of these studies have been performed on rodents, and very few studies on primates exist.…”