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Abstract
BackgroundBone marrow stromal cells (BMSCs) are pluripotent and thereby a potential candidate for cell replacement therapy for central nervous system degenerative disorders and traumatic injury. However, the mechanism of their differentiation and effect on neural tissues has not been fully elucidated. This study evaluates the effect of BMSCs on neural cell growth and survival in a retinal ganglion cell (RGCs) model by assessing the effect of changes in the expression of a BMSC-secreted protein, thrombospondin-1 (TSP-1), as a putative mechanistic agent acting on RGCs.Methods and FindingsThe effect of co-culturing BMSCs and RGCs in vitro was evaluated by measuring the following parameters: neurite outgrowth, RGC survival, BMSC neural-like differentiation, and the effect of TSP-1 on both cell lines under basal secretion conditions and when TSP-1 expression was inhibited. Our data show that BMSCs improved RGC survival and neurite outgrowth. Synaptophysin, MAP-2, and TGF-β expression are up-regulated in RGCs co-cultured with BMSCs. Interestingly, the BMSCs progressively displayed neural-like morphology over the seven-day study period. Restriction display polymerase chain reaction (RD-PCR) was performed to screen for differentially expressed genes in BMSCs cultured alone or co-cultured with RGCs. TSP-1, a multifactorial extracellular matrix protein, is critically important in the formation of neural connections during development, so its function in our co-culture model was investigated by small interfering RNA (siRNA) transfection. When TSP-1 expression was decreased with siRNA silencing, BMSCs had no impact on RGC survival, but reduced neurite outgrowth and decreased expression of synaptophysin, MAP-2 and TGF-β in RGCs. Furthermore, the number of BMSCs with neural-like characteristics was significantly decreased by more than two-fold using siRNA silencing.ConclusionsOur data suggest that the TSP-1 signaling pathway might have an important role in neural-like differentiation in BMSCs and neurite outgrowth in RGCs. This study provides new insights into the potential reparative mechanisms of neural cell repair.
Highlights
Bone marrow stromal cells (BMSCs) can self-renew,proliferate, and/or differentiate into a variety of cell types, such as cardiomyocytes, rhabdomyocytes, hepatocytes, osteocytes, chondrocytes, tencoytes, adipocytes, smooth muscle cells, and possibly even neural cells [1,2,3,4,5,6]
Our data suggest that the TSP-1 signaling pathway might have an important role in neural-like differentiation in BMSCs and neurite outgrowth in RGCs
Synaptophysin, MAP-2 and TGF-b expression were up-regulated in RGCs co-cultured with BMSCs compared to RGCs cultured alone
Summary
BMSCs can self-renew,proliferate, and/or differentiate into a variety of cell types, such as cardiomyocytes, rhabdomyocytes, hepatocytes, osteocytes, chondrocytes, tencoytes, adipocytes, smooth muscle cells, and possibly even neural cells [1,2,3,4,5,6]. Clinical trials with BMSCs are ongoing, and other clinical studies have been proposed to elucidate their usefulness [6,12,13,14,15,16]. Koc and colleagues concluded that patients with Hurler syndrome and metachromatic leukodystrophy, both associated with skeletal muscle and neurological manifestations, might experience a reversal of disease pathology in some tissues treated with allogeneic BMSC infusion [13]. (Baltimore, MD) has been granted ‘‘Fast Track’’ designation from the United States Food and Drug Administration; patients who have undergone bone marrow transplantation and experiencing graft-versus-host disease are being enrolled into a Phase III trial [16]. Bone marrow stromal cells (BMSCs) are pluripotent and thereby a potential candidate for cell replacement therapy for central nervous system degenerative disorders and traumatic injury. This study evaluates the effect of BMSCs on neural cell growth and survival in a retinal ganglion cell (RGCs) model by assessing the effect of changes in the expression of a BMSC-secreted protein, thrombospondin-1 (TSP-1), as a putative mechanistic agent acting on RGCs
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