Abstract
The progressive loss of endogenous regenerative capacity that accompanies mammalian aging has been attributed at least in part to alterations in the extracellular matrix (ECM) composition of adult tissues. Thus, creation of a more regenerative microenvironment, analogous to embryonic morphogenesis, may be achieved via pluripotent embryonic stem cell (ESC) differentiation and derivation of devitalized materials as an alternative to decellularized adult tissues, such as demineralized bone matrix (DBM). Transplantation of devitalized ESC materials represents a novel approach to promote functional tissue regeneration and reduce the inherent batch-to-batch variability of allograft-derived materials. In this study, the osteoinductivity of embryoid body-derived material (EBM) was compared to DBM in a standard in vivo ectopic osteoinduction assay in nude mice. EBM derived from EBs differentiated for 10 days with osteogenic media (+β-glycerophosphate) exhibited similar osteoinductivity to active DBM (osteoinduction score = 2.50 ± 0.27 vs. 2.75 ± 0.16) based on histological scoring, and exceeded inactive DBM (1.13 ± 0.13, p < 0.005). Moreover, EBM stimulated formation of new bone, ossicles, and marrow spaces, similar to active DBM. The potent osteoinductivity of EBM demonstrates that morphogenic factors expressed by ESCs undergoing osteogenic differentiation yield a novel devitalized material capable of stimulating de novo bone formation in vivo.
Highlights
Acellular and devitalized tissue therapies have been successfully used to promote endogenous repair to treat a variety of traumatic injuries and degenerative diseases
We demonstrate for the first time that embryonic stem cell (ESC)-derived materials contain osteoinductive and osteogenic factors (BMP-2, bone morphogenetic proteins (BMPs)-4, and vascular endothelial growth factor (VEGF)) capable of inducing new bone formation in vivo
The osteoinductivity of + β -glycerophosphate (β GP) embryoid bodies (EBs) materials (EBM) derived from osteogenic differentiated EBs was comparable to that of active Demineralized bone matrix (DBM), a commercially available and widely used osteoinductive material, by measures of mineralization, histologic osteoinduction score, and quantitative histomorphometry
Summary
Acellular and devitalized tissue therapies have been successfully used to promote endogenous repair to treat a variety of traumatic injuries and degenerative diseases. The osteoinductive potential of EBM was assessed using an in vivo mouse intramuscular implantation assay[6] by quantifying mineralization and the frequency of bone induction, as well as performing histomorphometric measurements of new bone formation in comparison with active and inactive DBM. This proof-of-principle work establishes a novel osteoinductive therapy exploiting the regenerative potential of ESC-derived materials that may be capable of stimulating de novo tissue formation for clinical applications aimed at ameliorating tissue injury or degeneration
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