Therapeutic benefits of young, but not old, adipose-derived mesenchymal stem cells in a chronic mouse model of bleomycin-induced pulmonary fibrosis

Abstract

The observation that pulmonary inflammatory lesions and bleomycin (BLM)-induced pulmonary fibrosis spontaneously resolve in young mice, while remaining irreversible in aged mice, suggests that impairment of pulmonary regeneration and repair is associated with aging. Since mesenchymal stem cells (MSCs) may promote repair following injury, we postulated that differences in MSCs from aged mice may underlie post-injury fibrosis in aging. The potential for young-donor MSCs to inhibit BLM-induced pulmonary fibrosis in aged male mice (>22 months) has not been studied. Adipose-derived MSCs (ASCs) from young (4-month) and old (22-month) male mice were infused 1-day following intratracheal BLM administration. At 21-day sacrifice, aged BLM mice demonstrated lung fibrosis by Ashcroft score, collagen content, and αv-integrin mRNA expression. Lung tissue from aged BLM mice receiving young ASCs exhibited decreased fibrosis, matrix metalloproteinase (MMP)-2 activity, oxidative stress, and markers of apoptosis vs. BLM controls. Lung mRNA expression of TNFα was also decreased in aged BLM mice receiving young-donor ASCs vs. BLM controls. In contrast, old-donor ASC treatment in aged BLM mice did not reduce fibrosis and related markers. On examination of the cells, young-donor ASCs had decreased mRNA expression of MMP-2, insulin-like growth factor receptor, and AKT activation compared to old-donor ASCs. These results show that the BLM-induced pulmonary fibrosis in aged mice could be blocked by young-donor ASCs and that the mechanisms involve changes in collagen turnover and markers of inflammation.

Oncostatin M-Preconditioned Mesenchymal Stem Cells Alleviate Bleomycin-Induced Pulmonary Fibrosis Through Paracrine Effects of the Hepatocyte Growth Factor

“…MSCs engrafted to an endotoxin‐induced lung injury model significantly attenuated pulmonary proinflammatory mediators while increasing the anti‐inflammatory cytokine IL‐10 []. MSC therapy inhibits the progression of BLM‐induced pulmonary fibrosis by altering proinflammatory cytokine tumor necrosis factor‐α and IL‐1β [, ] and by reducing the infiltration of inflammatory cells, such as neutrophils and lymphocytes [], in a paracrine way. Administration of MSC‐derived conditioned medium reduced the number of inflammatory cells and proinflammatory cytokine production within the BALF in hyperoxia‐induced lung injuries [].…”

Airway Transplantation of Adipose Stem Cells Protects against Bleomycin-Induced Pulmonary Fibrosis

“…However, in our study with young rats aged 3–4 months as both ADSC donors and recipients, we could not verify this point, as all animals in the BLM group showed high Aschroft scores. The genetic differences between species may have influenced this issue, as our study was conducted in rats and not mice 12. In any event, better assessment of this point will require specifically addressed studies.…”

Effects of inhalation and intravenous administration of allogeneic mesenchymal bone marrow stromal cells in a bleomycin-induced model of pulmonary fibrosis in rabbits

“…В пользу паракринных механизмов действия МСК свидетельствует и факт похожих результатов, достигаемых при введении кондиционной среды от МСК и прогениторных клеток в моделях легочного фиброза [18,19]. МСК от молодых мышей оказались более эффективны-ми в предотвращении развития легочного фиброза, чем выделенные от старых животных, за счет более активного подавления воспаления, оксидативного стресса и апоптоза через экспрессию противовос-палительных цитокинов [20]. Еще одним возмож-ным, хотя и мало изученным механизмом противо-воспалительного и антифиброзного действия МСК является межклеточный трансфер -когда экзогенно введенные клетки прикрепляются к поврежденно-му эпителию дыхательных путей и через микро-и наноканалы осуществляют доставку цитоплазмати-ческого и митохондриального материала, препятс-твующего апоптозу и способствующего восстанов-лению пораженной клетки [21,22].…”