Human mesenchymal stem cells express vascular cell phenotypes upon interaction with endothelial cell matrix

Abstract

Mesenchymal stem cells (MSCs) are thought to occupy a perivascular niche where they are exposed to signals originating from vascular cells. This study focused on the effects of endothelial cell (EC)-derived signals on MSC differentiation toward vascular cell lineages. Upon co-culture with two types of ECs, macrovascular (macro) ECs and microvascular (micro) ECs, the former caused MSCs to increase expression of both EC and smooth muscle cell (SMC) markers, while the latter induced expression of EC markers only. These marker changes in MSCs were linked to the extracellular matrixes secreted by the ECs (EC-matrix) rather than soluble EC-secreted factors. Beyond enhanced marker expression, EC-matrix also induced functional changes in MSCs indicative of development of a genuine vascular cell phenotype. These included enhanced incorporation into vessels and cytoskeletal localization of vascular SMC-specific contractile elements. The bioactivity of EC-matrix was sensitive to EDTA washes and required sulfated glycosaminoglycans. However, neither soluble VEGF nor substrate surfaces coated with fibronectin, collagen type IV, or laminin recreated the effects of EC-matrix on MSC vascular differentiation. In conclusion, these results identified EC-matrix as a critical regulator of vascular cell differentiation of MSCs. Elucidating these MSC-EC-matrix interactions and identifying the specific EC-matrix components involved will shed light on the perivascular signals seen by MSCs in vivo.

Pericytes, mesenchymal stem cells and their contributions to tissue repair

“…In addition, MSCs have been shown to upregulate paracrine factors such as integrin α7 and downregulate ICAM, VCAM and MCP11, which would favour specific wound healing by resident dermal fibroblasts which more closely represent the surrounding dermal tissue, thereby preventing fibrotic scar formation (Smith et al, 2010). In vitro, MSCs have also been shown to differentiate into different dermal cell types in the wound environment, such as epidermal cells, keratinocytes and microvascular ECs, which may present an additional mechanism by which MSCs prevent fibrosis (Lozito et al, 2009a).…”

Capillary-Like Network Formation by Human Amniotic Fluid-Derived Stem Cells Within Fibrin/Poly(Ethylene Glycol) Hydrogels

“…In addition, AFSC have a similar morphology, surface marker expression, and differentiation capacity compared to MSC, a proven source of perivascular cells, suggesting the potential use of AFSC as a vascular support cell source. 11,[14][15][16][17] Fibrin-based hydrogels stimulate vascularization and are used in clinical applications, such as growth factor delivery and cell encapsulation, making them an appropriate platform for assessing the vasculogenic potential of AFSC. 18 The main limitation associated with fibrin in tissue engineering is rapid degradation, which leads to loss of implant volume within days.…”

A Mathematical Model Predicting the Coculture Dynamics of Endothelial and Mesenchymal Stem Cells for Tissue Regeneration

“…20 Out of many different combinations of cells possessing regenerative potential, EC and MSC cocultures are among the most investigated for cardiovascular applications. 9,18 As recently discovered, when cocultured with ECs, MSCs exhibit the ability to actively interact with and support the formation of vascular tubular arrays. 9,14,20,32,33 Despite their popularity, however, the population dynamics of EC-MSC cocultures are still unclear.…”

“…12,13 MSCs were also shown, under certain in-vitro conditions, to trans-differentiate into ECs, [14][15][16] further reaffirming their in-vivo association. However, despite the ample literature reporting EC and stem cell cocultures, 3,5,17,18 no comprehensive investigation has explored and quantified their population dynamics, let alone investigated them together in a unifying model addressing the several factors influencing cell growth. Consequently, coculturing conditions such as medium composition, seeding densities, and ratios have been arbitrarily selected 9,18 or based on narrow 1 optimizations 8 that were reported without detailed reasoning.…”

“…However, despite the ample literature reporting EC and stem cell cocultures, 3,5,17,18 no comprehensive investigation has explored and quantified their population dynamics, let alone investigated them together in a unifying model addressing the several factors influencing cell growth. Consequently, coculturing conditions such as medium composition, seeding densities, and ratios have been arbitrarily selected 9,18 or based on narrow 1 optimizations 8 that were reported without detailed reasoning. Since blood supply of tissue constructs exceeding the diffusion barrier remains a critical problem, 19 shedding new light on the coculture dynamics of MSCs and ECs, two key players in angiogenesis and vasculogenesis, 20 should prove beneficial in cardiovascular applications.…”