NMDA receptor activation inhibits the antifibrotic effect of BM-MSCs on bleomycin-induced pulmonary fibrosis.

Abstract

Endogenous glutamate (Glu) release and N-methyl-d-aspartate (NMDA) receptor (NMDAR) activation are associated with lung injury in different animal models. However, the underlying mechanism is unclear. Bone marrow-derived mesenchymal stem cells (BM-MSCs), which show potential use for immunomodulation and tissue protection, play a protective role in pulmonary fibrosis (PF) process. Here, we found the increased Glu release from the BM cells of bleomycin (BLM)-induced PF mice in vivo. BLM stimulation also increased the extracellular Glu in BM-MSCs via the antiporter system xc- in vitro. The gene expression of each subunit of NMDAR was detected in BM-MSCs. NMDAR activation inhibited the proliferation, migration, and paracrine function of BM-MSCs in vitro. BM-MSCs were derived from male C57BL/6 mice, transfected with lentiviral vectors carrying the enhanced green fluorescence protein gene, pretreated with NMDA, and transplanted into the female recipient mice that were intratracheally injected with BLM to induce PF. Transplantation of NMDA-pretreated BM-MSCs significantly aggravated PF as compared with that in the normal BM-MSCs transplantation group. The sex determination gene Y chromosome and green fluorescence protein genes of BM-MSCs were detected to observe BM-MSCs homing in the fibrotic lungs. Moreover, NMDAR activation inhibited BM-MSC migration by downregulating the stromal cell-derived factor-1/C-X-C chemokine receptor type 4 signaling axis. NMDAR activation aggravated the transforming growth factor-β1-induced extracellular matrix production in alveolar epithelial cells and fibroblasts through the paracrine effects of BM-MSCs. In summary, these findings suggested that NMDAR activation-mediated Glu excitotoxicity induced by BLM in BM-MSCs abolished the therapeutic effects of normal BM-MSCs transplantation on BLM-induced PF.

• Authors: Xiaohong Li, Chen Li, Yiting Tang, Yanhong Huang, Qingmei Cheng, Xiaoting Huang, Feiyan Zhao, Caixia Hao, Dandan Feng, Jianping Xu, Jianzhong Han, Siyuan Tang, Wei Liu, Shaojie Yue, Ziqiang Luo
• Journal: American journal of physiology. Lung cellular and molecular physiology (Am J Physiol Lung Cell Mol Physiol) Vol. 315 Issue 3 Pg. L404-L421 (09 01 2018) ISSN: 1522-1504 [Electronic] United States
• PMID: 29722562 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, N-Methyl-D-Aspartate
• Bleomycin
• Glutamic Acid

Topics

• Animals
• Bleomycin (adverse effects, pharmacology)
• Bone Marrow Cells (metabolism, pathology)
• Cell Movement
• Cell Proliferation
• Gene Expression Regulation
• Glutamic Acid (metabolism)
• Male
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells (metabolism, pathology)
• Mice
• Paracrine Communication
• Pulmonary Fibrosis (chemically induced, metabolism, pathology, prevention & control)
• Receptors, N-Methyl-D-Aspartate (biosynthesis)