Reparative effect of mesenchymal stromal cells on endothelial cells after hypoxic and inflammatory injury

• Published in: Stem cell research & therapy Vol. 11; no. 1; pp. 1 - 352
• Main Authors: Sierra-Parraga, Jesus M, Merino, Ana, Eijken, Marco, Leuvenink, Henri, Ploeg, Rutger, Maller, Bjarne K, Jespersen, Bente, Baan, Carla C, Hoogduijn, Martin J
• Format: Journal Article
• Language: English
• Published: London BioMed Central Ltd 12.08.2020; BioMed Central; BMC
• Subjects: Angiogenesis; CD29 antigen; CD44 antigen; Cell adhesion & migration; Cell culture; Endothelial cells; Endothelium; Flow cytometry; Hypoxia; Inflammation; Ischemia; Ischemia-reperfusion-injury (IRI); Membrane permeability; Mesenchymal stem cells; Mesenchymal stromal cells (MSC); Mesenchyme; Molecular modelling; Oxidative stress; Paracrine signalling; Permeability; Physiological aspects; Pore size; Reperfusion; Secretome; Stem cells; Stromal cells; Tissue donation; Tissue repair; Transplantation; Tumor necrosis factor; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Umbilical vein; Wound healing; United States > US
• ISSN: 1757-6512; 1757-6512
• DOI: 10.1186/s13287-020-01869-3

Background The renal endothelium is a prime target for ischemia-reperfusion injury (IRI) during donation and transplantation procedures. Mesenchymal stromal cells (MSC) have been shown to ameliorate kidney function after IRI. However, whether this involves repair of the endothelium is not clear. Therefore, our objective is to study potential regenerative effects of MSC on injured endothelial cells and to identify the molecular mechanisms involved. Methods Human umbilical vein endothelial cells (HUVEC) were submitted to hypoxia and reoxygenation and TNF-[alpha] treatment. To determine whether physical interaction or soluble factors released by MSC were responsible for the potential regenerative effects of MSC on endothelial cells, dose-response experiments were performed in co-culture and transwell conditions and with secretome-deficient MSC. Results MSC showed increased migration and adhesion to injured HUVEC, mediated by CD29 and CD44 on the MSC membrane. MSC decreased membrane injury marker expression, oxidative stress levels, and monolayer permeability of injured HUVEC, which was observed only when allowing both physical and paracrine interaction between MSC and HUVEC. Furthermore, viable MSC in direct contact with injured HUVEC improved wound healing capacity by 45% and completely restored their angiogenic capacity. In addition, MSC exhibited an increased ability to migrate through an injured HUVEC monolayer compared to non-injured HUVEC in vitro. Conclusions These results show that MSC have regenerative effects on injured HUVEC via a mechanism which requires both physical and paracrine interaction. The identification of specific effector molecules involved in MSC-HUVEC interaction will allow targeted modification of MSC to apply and enhance the therapeutic effects of MSC in IRI. Keywords: Mesenchymal stromal cells (MSC), Ischemia-reperfusion-injury (IRI), Tissue repair, Angiogenesis, Endothelium