Microenvironmental Interaction Between Hypoxia and Endothelial Cells Controls the Migration Ability of Placenta‐Derived Mesenchymal Stem Cells via α4 Integrin and Rho Signaling

Abstract

Mesenchymal stem cells (MSCs) are a powerful source for cell therapy in degenerative diseases. The migration ability of MSCs is an important factor that enhances the therapeutic effect of the cells when they are transplanted into target tissues or organs. Hypoxia and the endothelial barrier, which are representative migration microenvironmental factors, are known to be regulated by the integrin-mediated pathway in several cancers. However, their regulatory mechanisms in MSCs remain unclear. Here, the objectives of the study were to compare the expression of markers related to integrin-mediated signaling in placenta-derived MSCs (PDMSCs) dependent on hypoxia and co-cultured with human umbilical vein endothelial cells (HUVECs) and to evaluate their correlations between migration ability and microenvironmetal factors including hypoxia and endothelial cells. The migration abilities of PDMSCs exposed to hypoxic conditions were significantly increased compared with normal fibroblasts (WI-38) and control (P < 0.05). Interestingly, decreased integrin α4 in PDMSCs under hypoxia induce to increase migration abilities of PDMSCs. Also, Rho family-related markers were significantly increased in PDMSCs under hypoxic conditions compared with normoxia (P < 0.05). Furthermore, the migration ability of PDMSCs was decreased by Rho kinase inhibitor treatment (Y-27632) and co-culturing with HUVECs in an ex vivo system. ROCK activity was increased by inhibiting integrin α4 with HUVECs and hypoxia compared with the absence of HUVECs and under normoxia. The findings suggest microenvironment event by hypoxia and the interaction with endothelial cells may be useful as a regulator of MSC migration and provide insight into the migratory mechanism of MSCs in stem cell-based therapy.

Concise Review: MSC Adhesion Cascade—Insights into Homing and Transendothelial Migration

“…Culture conditions, cell source, and manipulation can induce endogenous expression of surface and adhesion receptors . Expression profiles for surface receptors and thereby homing capabilities change considerably with culturing over several passages, and are further influenced by medium composition and oxygen concentration or pretreatment . For example, protein C kinase inhibitor Ro‐31‐8425 increases adhesion to ICAM binding domains of MSCs in vitro and in vivo .…”

Hypoxia Promotes Osteogenesis of Human Placental-Derived Mesenchymal Stem Cells

“…Placental-derived mesenchymal stem cells (pMSCs) are an intermediate between embryonic and adult stem cells (Jung et al 2013). Apart from the common characteristics of MSCs (selfrenewal, proliferation, and differentiation), pMSCs have their distinctive features: ease to collect in massive numbers, rapid expansion potential, and strong immunosuppressive property (Li et al 2007;Choi et al 2016). Moreover, because placenta is often discarded as waste after birth, pMSCs can be easily obtained without ethical concerns.…”

Replacement of Rat Tracheas by Layered, Trachea‐Like, Scaffold‐Free Structures of Human Cells Using a Bio‐3D Printing System

“…In fibroblast/HUVEC cocultures, fibroblasts presence decreased the apoptosis level of endothelial cells and generated an ECM, essential for luminal differentiation, whereas HUVECs formed multicell microvessels in spheroids . In MSC/fibroblast cocultures, MSCs promoted fibroblast proliferation and procollagen production, whereas endothelial cells regulated the MSC activity, migration, and differentiation, required to stabilize newly formed vasculature. Group F‐IV tubes had broader and longer fiber bundles than the other groups.…”