Human Umbilical Cord-Mesenchymal Stem Cells Combined With Low Dosage Nintedanib Rather Than Using Alone Mitigates Pulmonary Fibrosis in Mice

Abstract

Pulmonary fibrosis (PF) is a lethal pathological change of fibrotic interstitial lung diseases (ILDs) with abundant fibroblasts proliferation after severely or continually alveolar epithelial cells (AECs) injury. Barely therapies are helpful for PF. Here we use bleomycin intratracheally injection to model PF with or without human umbilical cord-mesenchymal stem cells (hUC-MSCs) and/or nintedanib intervention. RNA-Seq followed with real-time PCR and western blot were used to find out the specific possible mechanisms of the effects of hUC-MSC and nintedanib on PF. Immunostaining, cell counting kit-8 (CCK-8), and 5-bromo-2'-deoxyuridine (BrdU) incorporation assay were used to detect the cell proliferation in vivo or in vitro separately. We found that hUC-MSCs alone had prophylactic, but not therapeutic effects on bleomycin induced mouse PF. Nevertheless, the combination therapy of hUC-MSCs and low-dose nintedanib significantly improved survival and reversed lung fibrosis in PF model mice. The factors secreted by hUC-MSCs have promotional effects on the proliferation both of fibroblasts and AECs. Nintedanib could hamper the facilitation of fibroblasts caused by hUC-MSCs without influence on AECs proliferation, which might be related with the inhibition on FGFR, PDGFR, and VEGFR activities. Our study indicated that the combination therapy of hUC-MSCs and nintedanib should be a promising strategy for PF.

Keywords: cell proliferation; human umbilical cord–mesenchymal stem cells (hUC–MSCs); nintedanib; pulmonary fibrosis.