Growth/differentiation factor-5 promotes in vitro/vivo periodontal specific differentiation of induced pluripotent stem cell-derived mesenchymal stem cells

Abstract

Mesenchymal stem cells (MSCs) derived from induced pluripotent stem cells (iPSCs) represent a promising alternative source of MSCs for effective periodontal regeneration. Scientific evidence has demonstrated that growth/differentiation factor-5 (GDF-5) supports regeneration of periodontal tissues and has a key role in MSC differentiation. The present study investigated the effects of recombinant human GDF-5 (rhGDF-5) on periodontal specific differentiation of iPSC-derived MSCs (iPSC-MSCs) and bone marrow mesenchymal stem cells (BMSCs). rhGDF-5 treatment in vitro significantly enhanced the expression levels of marker genes associated with osteogenesis (OCN), fibrogenesis (periostin) and cementogenesis (CAP) in the iPSC-MSCs compared with untreated controls (all P<0.05). Interestingly, the rhGDF-5-treated BMSCs failed to exhibit overexpression of periostin and CAP despite highly upregulated expression of OCN. In the presence of rhGDF-5, both the iPSC-MSCs and BMSCs demonstrated marked formation of mineralized nodules. Notably, rhGDF-5 greatly promoted periodontal specific differentiation of the iPSC-MSCs encapsulated in hyaluronic acid (HA) hydrogels in vivo as determined by immunohistochemical and immunofluorescence staining. The majority of the PKH67-labeled iPSC-MSCs implanted with rhGDF-5 exhibited strong expression of OCN, periostin and CAP. In conclusion, iPSC-MSCs demonstrate high periodontal specific differentiation potential in response to rhGDF-5 both in vitro and in vivo. The delivery of iPSC-MSCs and rhGDF-5 with HA hydrogel may have beneficial effects in regenerative periodontal therapy.