Bone morphogenetic protein-2-independent bone formation by human iPSC-derived megakaryocytes and platelets

Abstract

Bone regeneration (BR) is an ongoing challenge in biomedical research. While recombinant human bone morphogenetic protein-2 (rhBMP-2) is available for clinical use, its side effects remain a concern. Patient-derived platelet-rich plasma has been proposed as an alternative, but its heterogeneity poses a major hurdle to standardization. Here, we evaluated the effectiveness of induced pluripotent stem cell (iPSC)-derived megakaryocytes and platelets (iMPs) and recombinant human bone morphogenetic protein-2 (rhBMP-2) as potential BR therapy in a rat lumbar bone graft model. We implanted artificial bones with iMPs and/or rhBMP-2 and performed computed tomography and histological analysis to assess new bone formation. iMPs and rhBMP-2 showed comparable efficacy in vivo, but rhBMP-2 induced significant inflammation. In vitro, iMPs promoted human bone marrow mesenchymal stem cell (BM-MSC) proliferation and migration, while rhBMP-2 enhanced osteodifferentiation. RNA sequencing revealed cell cycle-related gene upregulation by iMPs. Altogether, these findings suggest iMPs, alone or in combination with rhBMP-2, as a promising BR therapy for enhancing clinical efficacy.

Keywords: Bone; Bone morphogenetic protein-2; Induced pluripotent stem cells; Megakaryocytes; Mesenchymal stem cells; Platelet-rich plasma; Platelets.