Activation of Notch1 signaling alleviates dysfunction of bone marrow-derived mesenchymal stem cells induced by cigarette smoke extract

Abstract

Bone marrow-derived mesenchymal stem cells (BM-MSCs) are considered attractive therapeutic agents for the treatment of COPD. However, little is known about the impact of Notch on the proliferation, migration, and survival of MSCs in a cigarette smoke (CS) microenvironment. Here, we used CS extract to mimic the CS microenvironment in vitro, with the intention to investigate the effect of Notch in regulating proliferation, migration, and survival of BM-MSCs. Rat bone marrow mesenchymal stem cells were infected with lentivirus vector containing the intracellular domain of Notch1 (N1ICD) and challenged with CS extract. Cell proliferation was detected by Ki67 staining and expression of cell cycle-related proteins. A transwell assay was used to measure cell migration and the expression of apoptotic proteins was examined. The proliferation of BM-MSCs overexpressing N1ICD significantly increased. Consistently, levels of cyclin D1, p-Rb, and E2F-1 increased in N1ICD overexpressing cells. N1ICD overexpression also increased cell migration compared with the control group. N1ICD overexpression equilibrated the expression of Bax and Bcl-2, and blocked caspase-3 cleavage, contributing to the inhibition of apoptosis. Moreover, blockade of the PI3K/Akt pathway suppressed the aforementioned cytoprotective effects of N1ICD. In conclusion, activation of Notch signaling improved proliferation, migration, and survival of BM-MSCs in a CS microenvironment partly through the PI3K/Akt pathway.

Keywords:

• mesenchymal stem cells
• chronic obstructive pulmonary disease
• cigarette smoke extract
• Notch

Supplementary material

Figure S1 Isolated MSCs presented a fibroblast-like shape (A) and exhibited adipocyte (B), osteoblast (C), and chondrocyte (D) differentiation capacity.

Abbreviation: MSC, mesenchymal stem cells.

Acknowledgments

This work was supported by the National Natural Science Foundation of China (No. 81470232) (www.nsfc.gov.cn). The study was also supported by the Natural Science Foundation of Shanghai (No. 17ZR1418400) and (No. 14401970500).

Disclosure

The authors report no conflicts of interest in this work.