Abstract
The successful implementation of adipose-derived mesenchymal stem cells (ADSCs) in bone regeneration depends on efficient osteogenic differentiation. However, a literature survey and our own experience demonstrated that current differentiation methods are not effective enough. Since the differentiation of mesenchymal stem cells (MSCs) into osteoblasts and adipocytes can be regulated by cyclic adenosine monophosphate (cAMP) signaling, we investigated the effects of cAMP activator, forskolin, and inhibitor, SQ 22,536, on the early and late osteogenic differentiation of ADSCs cultured in spheroids or in a monolayer. Intracellular cAMP concentration, protein kinase A (PKA) activity, and inhibitor of DNA binding 2 (ID2) expression examination confirmed cAMP up- and downregulation. cAMP upregulation inhibited the cell cycle and protected ADSCs from osteogenic medium (OM)-induced apoptosis. Surprisingly, the upregulation of cAMP level at the early stages of osteogenic differentiation downregulated the expression of osteogenic markers RUNX2, Osterix, and IBSP, which was more significant in spheroids, and it is used for the more efficient commitment of ADSCs into preosteoblasts, according to the previously reported protocol. However, cAMP upregulation in a culture of ADSCs in spheroids resulted in significantly increased osteocalcin production and mineralization. Thus, undifferentiated and predifferentiated ADSCs respond differently to cAMP pathway stimulation in terms of osteogenesis, which might explain the ambiguous results from the literature.
Highlights
Adipose-derived mesenchymal stem cells (ADSCs) are a subtype of mesenchymal stem cells (MSCs) that reside in the stromal vascular fraction (SVF) of adipose tissue
This study reported effective bone callus formation in experiment animals treated with bone marrow-derived mesenchymal stem cells (BMSCs) as that with BMSC-conditioned medium [6], which indicated that cell-derived secreted factors were responsible for callus formation
The osteogenic-differentiation process of MSCs, and ADSCs in particular, needs to be studied further, with the aim to develop an improved method of bone-forming cells in vitro and in vivo
Summary
Adipose-derived mesenchymal stem cells (ADSCs) are a subtype of mesenchymal stem cells (MSCs) that reside in the stromal vascular fraction (SVF) of adipose tissue. ADSCs are being extensively studied in preclinical and clinical trials, aiming to provide a tool for the treatment of a number of human disorders. These disorders include soft-tissue defects, cardiovascular diseases, neurological impairments, autoimmunological diseases, and skeletal defects [1]. ADSCs secrete an array of soluble factors, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF), bone morphogenetic protein 2 (BMP2), and matrix metalloproteinases that stimulate neovascularization, wound healing, matrix remodeling, and osteoblast-precursor differentiation.
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