Phenotype-based selection of bone marrow mesenchymal stem cell-derived smooth muscle cells for elastic matrix regenerative repair in abdominal aortic aneurysms

Chronic proteolytic disruption of elastic fibres within the abdominal aortic wall results in wall vessel expansion to form rupture-prone abdominal aortic aneurysms (AAA). Arresting AAA growth is not possible as adult vascular smooth muscle cells (SMCs) poorly auto-regenerate and repair elastic fibres. Thus, there is a need to identify alternate cell sources capable of robust elastic matrix assembly to overcome elastolysis in the AAA wall. Previously, we demonstrated the superior elastogenic properties of rat bone marrow mesenchymal stem cell (BM-MSC)-derived SMCs (BM-SMCs) relative to aneurysmal and healthy rat aortic SMCs. In the present study, we investigate how phenotypic coordinates of the derived BM-SMCs, in turn dependent on conditions of BM-MSC differentiation, impact their elastic matrix synthesis abilities. More specifically, we investigated how glucose content, serum levels and the presence of transforming growth factor (TGF)-β1 supplements alone or together with platelet-derived growth factor (PDGF-BB) in the differentiation medium influence phenotype of, and elastogenesis by derived rat BM-SMCs. BM-SMCs generated in low-glucose and 10% v/v serum conditions in the presence of TGF-β1 with or without PDGF-BB exhibited a mature phenotype characterized by contractility and migrative tendencies similar to healthy rat aortic SMCs, and yet capable of robust tropoelastin (precursor) synthesis and assembly of a fibrous, highly crosslinked elastic matrix. Thus, we have identified metrics and conditions for selecting BM-SMCs with superior elastogenesis for in situ elastic matrix regeneration. Future studies will focus on characterizing these specific BM-SMC subtypes for their pro-elastogenic and anti-proteolytic effects on aneurysmal SMCs to confirm their preferred use for therapy aimed at AAA tissue regenerative repair.