Abstract
Bone regeneration is a complex, well-orchestrated process based on the interactions between osteogenesis and angiogenesis, observed in both physiological and pathological situations. However, specific conditions (e.g., bone regeneration in large quantity, immunocompromised regenerative process) require additional support. Tissue engineering offers novel strategies. Bone regeneration requires a cell source, a matrix, growth factors and mechanical stimulation. Regenerative cells, endowed with proliferation and differentiation capacities, aim to recover, maintain, and improve bone functions. Vascularization is mandatory for bone formation, skeletal development, and different osseointegration processes. The latter delivers nutrients, growth factors, oxygen, minerals, etc. The development of mesenchymal stromal cells (MSCs) and endothelial progenitor cells (EPCs) cocultures has shown synergy between the two cell populations. The phenomena of osteogenesis and angiogenesis are intimately intertwined. Thus, cells of the endothelial line indirectly foster osteogenesis, and conversely, MSCs promote angiogenesis through different interaction mechanisms. In addition, various studies have highlighted the importance of the microenvironment via the release of extracellular vesicles (EVs). These EVs stimulate bone regeneration and angiogenesis. In this review, we describe (1) the phenomenon of bone regeneration by different sources of MSCs. We assess (2) the input of EPCs in coculture in bone regeneration and describe their contribution to the osteogenic potential of MSCs. We discuss (3) the interaction mechanisms between MSCs and EPCs in the context of osteogenesis: direct or indirect contact, production of growth factors, and the importance of the microenvironment via the release of EVs.
Highlights
Bone regeneration is a complex, well-orchestrated process based on the interactions between osteogenesis and angiogenesis (Fröhlich, 2019), observed in both physiological and pathological situations
Since 2001, when the first three patients were successfully treated for bone defects with expanded autologous bone marrow mesenchymal stromal cells (BM-MSCs) (Quarto et al, 2001), numerous studies have been conducted (Watson et al, 2014; Perez et al, 2018)
Preclinical and clinical studies have demonstrated that MSCs have added value in bone regeneration
Summary
Bone regeneration is a complex, well-orchestrated process based on the interactions between osteogenesis and angiogenesis (Fröhlich, 2019), observed in both physiological and pathological situations. Since 2001, when the first three patients were successfully treated for bone defects with expanded autologous bone marrow mesenchymal stromal cells (BM-MSCs) (Quarto et al, 2001), numerous studies have been conducted (Watson et al, 2014; Perez et al, 2018). Different mesenchymal stromal cells (MSCs) sources have been studied in bone tissue engineering in both clinical and preclinical settings (Perez et al, 2018). MSCs are defined by the three following criteria: adherence to plastic, specific surface antigen (Ag) expression, and multipotent differentiation potential, according to the International Society for Cellular Therapy (ISCT) (Figure 1; Dominici et al, 2006) They exhibit great differentiation potential into many different types of tissue lineages, including bone (osteoblasts), cartilage (chondrocytes), muscle (myocytes), and fat (adipocytes). In 2006, a first patient suffering from compartment syndrome and bone non-union was treated by autologous BM-MNC implantation for therapeutic angiogenesis and subsequent bone regeneration. Hip replacement was performed in 94/534 cases (17.6%) after
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