Abstract
BackgroundCellular therapy based on mesenchymal stem cells (MSCs) is a promising novel therapeutic strategy for the osteonecrosis of the femoral head (ONFH), which is gradually becoming popular, particularly for early-stage ONFH. Nonetheless, the MSC-based therapy is challenging due to certain limitations, such as limited self-renewal capability of cells, availability of donor MSCs, and the costs involved in donor screening. As an alternative approach, MSCs derived from induced pluripotent stem cells (iPSCs), which may lead to further standardized-cell preparations.MethodsIn the present study, the bone marrow samples of patients with ONFH (n = 16) and patients with the fracture of the femoral neck (n = 12) were obtained during operation. The bone marrow-derived MSCs (BMSCs) were isolated by density gradient centrifugation. BMSCs of ONFH patients (ONFH-BMSCs) were reprogrammed to iPSCs, following which the iPSCs were differentiated into MSCs (iPSC-MSCs). Forty adult male rats were randomly divided into following groups (n = 10 per group): (a) normal control group, (b) methylprednisolone (MPS) group, (c) MPS + BMSCs treated group, and (d) MPS + iPSC-MSC-treated group. Eight weeks after the establishment of the ONFH model, rats in BMSC-treated group and iPSC-MSC-treated group were implanted with BMSCs and iPSC-MSCs through intrabone marrow injection. Bone repair of the femoral head necrosis area was analyzed after MSC transplantation.ResultsThe morphology, immunophenotype, in vitro differentiation potential, and DNA methylation patterns of iPSC-MSCs were similar to those of normal BMSCs, while the proliferation of iPSC-MSCs was higher and no tumorigenic ability was exhibited. Furthermore, comparing the effectiveness of iPSC-MSCs and the normal BMSCs in an ONFH rat model revealed that the iPSC-MSCs was equivalent to normal BMSCs in preventing bone loss and promoting bone repair in the necrosis region of the femoral head.ConclusionReprogramming can reverse the abnormal proliferation, differentiation, and DNA methylation patterns of ONFH-BMSCs. Transplantation of iPSC-MSCs could effectively promote bone repair and angiogenesis in the necrosis area of the femoral head.
Highlights
Cellular therapy based on mesenchymal stem cells (MSCs) is a promising novel therapeutic strategy for the osteonecrosis of the femoral head (ONFH), which is gradually becoming popular, for early-stage Osteonecrosis of the femoral head (ONFH)
Induction of induced pluripotent stem cells (iPSCs) from ONFH-bone marrow-derived MSCs (BMSCs) MSCs were isolated from the bone marrow samples of the ONFH patients (ONFH-BMSCs), and the culture was expanded for three passages
It is possible to reprogram human skin fibroblasts into iPSCs [35], BMSCs were selected as donor cells for reprogramming in the present study, firstly because of the convenience of obtaining materials when the ONFH patients are undergoing total hip arthroplasty without secondary trauma, and secondly, because BMSCs are adult stem cells and may be easier to reprogram compared to terminally differentiated somatic cells
Summary
Cellular therapy based on mesenchymal stem cells (MSCs) is a promising novel therapeutic strategy for the osteonecrosis of the femoral head (ONFH), which is gradually becoming popular, for early-stage ONFH. The usual cause of ONFH is the inadequate blood supply to the trabecular bone in the femoral head, leading to bone cell death due to various factors, such as excessive alcohol consumption, hormone application, trauma, and diseases of connective tissue, which is followed by the collapse of the articular cartilage and subsequent osteoarthritis [1,2,3,4,5,6]. If timely treatment is not received, ONFH would lead to the collapse of the femoral head, which requires total hip arthroplasty (THA) [8]. The pathogenesis of ONFH is not clearly understood, certain recent studies have demonstrated a strong association between ONFH and the reduction or alterations of BMSCs or other progenitor cells in the proximal femur, and it is gradually accepted that ONFH originates at the cellular level [10,11,12,13,14,15]
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