The paracrine effects of human induced pluripotent stem cells promote bone-like structures via the upregulation of BMP expression in a mouse ectopic model

Abstract

Use of human induced pluripotent stem cells (h-iPSCs) for bone tissue engineering is most appealing, because h-iPSCs are an inexhaustible source of osteocompetent cells. The present study investigated the contribution of undifferentiated h-iPSCs and elucidated aspects of the underlying mechanism(s) of the involvement of these cells to new bone formation. Implantation of undifferentiated h-iPSCs seeded on coral particles in ectopic sites of mice resulted in expression of osteocalcin and DMP-1, and in mineral content similar to that of the murine bone. The number of the implanted h-iPSCs decreased with time and disappeared by 30 days post-implantation. In contrast, expression of the murine osteogenic genes at day 15 and 30 post-implantation provided, for the first time, evidence that the implanted h-iPSCs affected the observed outcomes via paracrine mechanisms. Supporting evidence was provided because supernatant conditioned media from h-iPSCs (h-iPSC CM), promoted the osteogenic differentiation of human mesenchymal stem cells (h-MSCs) in vitro. Specifically, h-iPSC CM induced upregulation of the BMP-2, BMP-4 and BMP-6 genes, and promoted mineralization of the extracellular matrix. Given the current interest in the use of h-iPSCs for regenerative medicine applications, our study contributes new insights into aspects of the mechanism underlying the bone promoting capability of h-iPSCs.

Human Adipose-derived Pericytes Display Steroidogenic Lineage Potential in Vitro and Influence Leydig Cell Regeneration in Vivo in Rats

“…We acknowledge that our studies used a relatively small number of immunocompetent animals without immunosuppression, which may have enhanced the inflammatory response to Leydig cell death post EDS treatment due to xenogeneic rejection. However, previous studies of xenogenic transplantation in immuno-deficient models also noted limited survival and differentiation of transplanted stem cells, despite positive effects on tissue regeneration 56,60,61 . Additionally, the hAd-PSCs used in this study were derived from a single donor which may confound our assessment of the regenerative capacity of hAd-PSCs as donor age and sex may influence hAd-PSC activity 62 .…”

Rat sinus mucosa‐ and periosteum‐derived exosomes accelerate osteogenesis

“…The cell fate and osteogenic ability of BM‐MSCs can be affected by the surrounding microenvironment. Thus far, many studies on bone regeneration have focused on paracrine effects (C. Li, Li, Liu, Zhou, & Zhou, ; Oudina et al, ). In our study, we demonstrated that the paracrine factors, especially exosomes derived from PCs and SMCs can accelerate osteogenesis both in vivo and in vitro.…”

Induced Pluripotent Stem Cells in Dental and Nondental Tissue Regeneration: A Review of an Unexploited Potential

“…To settle these conflicting trends, the authors investigated the paracrine effect of bioactive CM from human iPSCs. Interestingly, human iPSC CM promoted the osteogenic differentiation of human MSC osteogenic differentiation as well as upregulated the expression of BMP-2, BMP-4, and BMP-6 genes and enhanced extracellular matrix mineralization [122].…”

“…3ions in a permissive environment through various signaling pathways [107]. Similarly, ectopically implanted human iPSCs seeded on coral scaffolds in mice demonstrated the expression of bone-like structures through the release of osteoinductive factors including BMPs [122]. Paradoxically, the rapid disappearance of human iPSCs due to early cell death was associated with an increase in the osteogenic genes.…”

“…The paracrine role of iPSCs in salivary gland regeneration has been proven upon coculturing embryonic submandibular gland cells and mouse iPSCs [124]. Besides, human iPSC CM promoted the osteogenic differentiation of human MSCs [122]. Usage of iPSC-derived secretome for tissue regeneration merits further research such as determining the active genes and growth factors expressed in CM from iPSCs.…”