Resistance of transplanted mesenchymal stem cells (MSCs) in post-ischemic heart is limited by their poor vitality.
Vascular-endothelial-growth-factor-A (
VEGF-A) as such or slowly released by
fibronectin-coated pharmacologically-active-microcarriers (FN-PAM-
VEGF) could differently affect survival
kinases and anti-apoptotic mediator (e.g. Bcl-2). Therefore
VEGF-A or FN-PAM-
VEGF could differently enhance cell proliferation, and/or resistance to
hypoxia/reoxygenation (H/R) of MSCs. To test these hypotheses MSCs were incubated for 6-days with
VEGF-A alone or with FN-PAM-
VEGF. In addition, MSCs pre-treated for 24-hrs with
VEGF-A or FN-PAM-
VEGF were subsequently exposed to H/R (72-hrs 3% O(2) and 3-hrs of reoxygenation). Cell-proliferation and post-hypoxic vitality were determined.
Kinases were studied at 30-min., 1- and 3-days of treatment. Cell-proliferation increased about twofold (P < 0.01) 6-days after
VEGF-A treatment, but by a lesser extent (55% increase) with FN-PAM-
VEGF (P < 0.05). While MSC pre-treatment with
VEGF-A confirmed cell-proliferation, pre-treatment with FN-PAM-
VEGF protected MSCs against H/R. In the early phase of treatments,
VEGF-A increased phospho-Akt, phospho-ERK-1/2 and phospho-PKCĪµ compared to the untreated cells or FN-PAM-
VEGF. Afterword,
kinase phosphorylations were higher with VGEF, except for ERK-1/2, which was similarly increased by both treatments at 3 days. Only FN-PAM-
VEGF significantly increased Bcl-2 levels. After H/R,
lactate dehydrogenase release and cleaved
Caspase-3 levels were mainly reduced by FN-PAM-
VEGF. While
VEGF-A enhances MSC proliferation in normoxia, FN-PAM-
VEGF mainly hampers post-hypoxic MSC death. These different effects underscore the necessity of approaches suited to the various conditions. The use of FN-PAM-
VEGF could be considered as a novel approach for enhancing MSC survival and regeneration in hostile environment of post-ischemic tissues.