Vascular endothelial growth factor secretion and immunosuppression are distinct potency mechanisms of human bone marrow mesenchymal stromal cells

• Published in: Stem cells (Dayton, Ohio) Ohio), 2024-08, Vol.42 (8), p.736-751
• Main Authors: Faircloth, Tyler U, Temple, Sara, Parr, Rhett N, Tucker, Anna B, Rajan, Devi, Hematti, Peiman, Kugathasan, Subra, Chinnadurai, Raghavan
• Format: Article
• Language: English
• Subjects: Bone Marrow Cells - cytology; Bone Marrow Cells - metabolism; Cells, Cultured; Coculture Techniques; Humans; Immunosuppression Therapy; Mesenchymal Stem Cells - cytology; Mesenchymal Stem Cells - metabolism; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 1066-5099; 1549-4918; 1549-4918
• DOI: 10.1093/stmcls/sxae040

Mesenchymal stromal cells (MSCs) are investigated as cellular therapeutics for inflammatory bowel diseases and associated perianal fistula, although consistent efficacy remains a concern. Determining host factors that modulate MSCs' potency including their secretion of angiogenic and wound-healing factors, immunosuppression, and anti-inflammatory properties are important determinants of their functionality. We investigated the mechanisms that regulate the secretion of angiogenic and wound-healing factors and immune suppression of human bone marrow MSCs. Secretory analysis of MSCs focusing on 18 angiogenic and wound-healing secretory molecules identified the most abundancy of vascular endothelial growth factor A (VEGF-A). MSC viability and secretion of other angiogenic factors are not dependent on VEGF-A secretion which exclude the autocrine role of VEGF-A on MSC's fitness. However, the combination of inflammatory cytokines IFNγ and TNFα reduces MSC's VEGF-A secretion. To identify the effect of intestinal microvasculature on MSCs' potency, coculture analysis was performed between human large intestine microvascular endothelial cells (HLMVECs) and human bone marrow-derived MSCs. HLMVECs do not attenuate MSCs' viability despite blocking their VEGF-A secretion. In addition, HLMVECs neither attenuate MSC's IFNγ mediated upregulation of immunosuppressive enzyme indoleamine 2,3-dioxygenase nor abrogate suppression of T-cell proliferation despite the attenuation of VEGF-A secretion. We found that HLMVECs express copious amounts of endothelial nitric oxide synthase and mechanistic analysis showed that pharmacological blocking reverses HLMVEC-mediated attenuation of MSC's VEGF-A secretion. Together these results suggest that secretion of VEGF-A and immunosuppression are separable functions of MSCs which are regulated by distinct mechanisms in the host.