Abstract P229: Stabilizing Efects of Human Mesenchymal Stem Cells on Vascular Integrity After Trauma are Mediated Through Soluble Factors That Act Systemically
Multiple therapeutic applications of bone marrow derived mesenchymal stem cells (MSCs) have been reported. However, little is known about interactions between MSCs and endothelial cells (ECs), the first cell type that they interact with when administered intravenously for therapeutic applications.
Hypothesis: We hypothesized that MSCs have stabilizing effects on ECs that prevent endothelial permeability and vascular disassembly after injury.
Methods: To determine the effects of MSCs on ECs in vitro, MSCs were co-cultured with HUVECs (ECs) at a ratio of 1:5 MSC:EC in the same well or in transwells and compared with ECs cultured alone. ECs were separated and subjected to in vitro tests of vascular tube stability, proliferation and permeability. To study the effects of MSCs on vascular integrity in vivo, we used a mouse model of traumatic brain injury (TBI) which produces blood brain barrier (BBB) compromise, and also used a rat model of hemorrhagic shock which produces pulmonary vascular compromise.
Results: MSCs decrease EC proliferation (10%), prevent EC vascular tube breakdown by 50%, and inhibit EC permeability in vitro by 30%. These effects require EC-MSC contact and are meditated by soluble factor(s). MSC-EC interactions result in enhanced expression and co-localization of VE-cadherin and β-catenin at the cell membrane. Disruption of VE-cadherin-β-catenin interaction abrogates the observed effects. As an in vivo correlate we show that intravenously administered MSCs after TBI reduce BBB permeability by 50% compared with vehicle control. MSC treatment resulted in a 56% increase in VE-cadherin expression in the injured penumbra. In a rodent model of hemorrhagic shock (HS) we find that pretreatment with intravenously administered MSCs prevented the ablation of endothelial junctional proteins VE-Cadherin, Claudin-1, and Claudin-5 in the lungs.
Conclusion: We show here that MSCs exert significant stabilizing effects on ECs and vasculature. These results identify a previously undefined mechanism of action of MSCs involving contact dependent EC interaction and modulation of the endothelial barrier, and bring attention to the potentially beneficial effects of MSCs as a resuscitative adjunct in traumatic injury.