Mitigation of radiation-induced hematopoietic injury via regulation of cellular MAPK/phosphatase levels and increasing hematopoietic stem cells

Here we describe a novel strategy for mitigation of ionizing radiation-induced hematopoietic syndrome by suppressing the activity of MKP3, resulting in ERK activation and enhanced abundance of hematopoietic stem cells, using the antioxidant flavonoid baicalein (5,6,7-trihydroxyflavone). It offered complete protection to mouse splenic lymphocytes against radiation-induced cell death. Inhibitors of ERK and Nrf-2 could significantly abrogate baicalein-mediated radioprotection in lymphocytes. Baicalein inhibited phosphatase MKP3 and thereby enhanced phosphorylation of ERK and its downstream proteins such as Elk and Nrf-2. It also increased the nuclear levels of Nrf-2 and the mRNA levels of its dependent genes. Importantly, baicalein administration to mice before radiation exposure led to significant recovery of loss of bone marrow cellularity and also inhibited cell death. Administration of baicalein increased the hematopoietic stem cell frequency as measured by side-population assay and also by antibody staining. Further, baicalein offered significant protection against whole-body irradiation (WBI; 7.5 Gy)-induced mortality in mice. Interestingly, we found that baicalein works by activating the same target molecules ERK and Nrf-2 both in vitro and in vivo. Finally, administration of all-trans-retinoic acid (inhibitor of Nrf-2) significantly abrogated baicalein-mediated protection against WBI-induced mortality in mice. Thus, in contrast to the generalized conception of antioxidants acting as radioprotectors, we provide a rationale that antioxidants exhibit pleiotropic effects through the activation of multiple cellular signaling pathways.     

Tumor endothelial marker 5 expression in endothelial cells during capillary morphogenesis is induced by the small GTPase Rac and mediates contact inhibition of cell proliferation

Tumor endothelial marker (TEM) 5 is an adhesion G-protein-coupled receptor upregulated in endothelial cells during tumor and physiologic angiogenesis. So far, the mechanisms leading to upregulation of TEM5 and its function during angiogenesis have not been identified. Here, we report that TEM5 expression in endothelial cells is induced during capillary-like network formation on Matrigel, during capillary morphogenesis in a three-dimensional collagen I matrix, and upon confluence on a two-dimensional matrix. TEM5 expression was not induced by a variety of soluble angiogenic factors, including VEGF and bFGF, in subconfluent endothelial cells. TEM5 upregulation was blocked by toxin B from Clostridium difficile, an inhibitor of the small GTPases Rho, Rac, and Cdc42. The Rho inhibitor C3 transferase from Clostridium botulinum did not affect TEM5 expression, whereas the Rac inhibitor NSC23766 suppressed TEM5 upregulation. An excess of the soluble TEM5 extracellular domain or an inhibitory monoclonal TEM5 antibody blocked contact inhibition of endothelial cell proliferation resulting in multilayered islands within the endothelial monolayer and increased vessel density during capillary formation. Based on our results we conclude that TEM5 expression during capillary morphogenesis is induced by the small GTPase Rac and mediates contact inhibition of proliferation in endothelial cells.     

WJSC 6th Anniversary Special Issues（2）:Mesenchymal stem cells Progress of mesenchymal stem cell therapy for neural and retinal diseases

Complex circuitry and limited regenerative power make central nervous system(CNS)disorders the most challenging and difficult for functional repair.With elusive disease mechanisms,traditional surgical and medical interventions merely slow down the progression of the neurodegenerative diseases.However,the number of neurons still diminishes in many patients.Recently,stem cell therapy has been proposed as a viable option.Mesenchymal stem cells(MSCs),a widely-studied human adult stem cell population,have been discovered for more than 20 years.MSCs have been found all over the body and can be conveniently obtained from different accessible tissues:bone marrow,blood,and adipose and dental tissue.MSCs have high proliferative and differentiation abilities,providing an inexhaustible source of neurons and glia for cell replacement therapy.Moreover,MSCs also show neuroprotective effects without any genetic modification or reprogramming.In addition,the extraordinary immunomodulatory properties of MSCs enable autologous and heterologous transplantation.These qualities heighten the clinical applicability of MSCs when dealing with the pathologies of CNS disorders.Here,we summarize the latest progress of MSC experimental research as well as human clinical trials for neural and retinal diseases.This review article will focus on multiple sclerosis,spinal cord injury,autism,glaucoma,retinitis pigmentosa and age-related macular degeneration.