Abstract
BackgroundAdipose-derived stem cells (ADSCs) are an attractive cell source for bone tissue engineering and have great potential for bone regeneration and defect repair. The transcriptional coactivator with PDZ-binding motif (TAZ) has been demonstrated to modulate osteogenic and adipogenic differentiation of mesenchymal stem cells. However, its roles during ADSC differentiation and therapeutic potentials for bone regeneration have as yet not been well established.MethodsTAZ expression was measured during osteogenic differentiation of ADSCs in vitro. Both loss-of-function and gain-of-function approaches by TAZ knockdown or enforced overexpression were utilized to determine its functions during osteogenic differentiation of ADSCs. TM-25659, a chemical activator of TAZ, was used to determine whether pharmacological activation of TAZ in ADSCs enhanced osteogenic differentiation in vitro and bone formation in animal models. The molecular mechanisms underlying TAZ in promoting osteogenesis of ADSCs were also explored.ResultsIncreased TAZ expression was observed during osteogenic differentiation of human ADSCs. TAZ knockdown resulted in compromised osteogenic differentiation and enhanced adipogenic differentiation of ADSCs. In contrast, enforced TAZ overexpression yielded increased osteogenic differentiation and bone regeneration in vivo, and impaired adipogenic differentiation of ADSCs. Pharmacological activation of TAZ by its chemical activator TM-25659 facilitated osteogenic differentiation of ADSCs. Noticeably, transient treatment of ADSCs with TM-25659 or intraperitoneal injection of TM-25659 significantly enhanced bone regeneration of ADSCs loaded with porous β-TCP in vivo. Mechanistically, TM-25659 exposure significantly promoted TAZ phosphorylation and nuclear translocation, and potentiated the assembly of the TAZ-Runx2 complex. Subsequently, the TAZ-Runx2 complex was further recruited to the promoter of osteocalcin and in turn enhanced its transcription.ConclusionsOur findings indicate that TAZ is a key mediator that promotes ADSC commitment to the osteoblast lineage. Pharmacological activation of TAZ in ADSCs might become a feasible and promising approach to enhance bone regeneration and repair.
Highlights
Adipose-derived stem cells (ADSCs) are an attractive cell source for bone tissue engineering and have great potential for bone regeneration and defect repair
transcriptional coactivator with PDZ-binding motif (TAZ) is upregulated during osteogenic differentiation while it is downregulated during adipogenic differentiation of ADSCs Accumulating evidence has indicated that TAZ is critically involved in stem cell self-renewal and differentiation in embryonic and mesenchymal stem cell (MSC) [17, 20, 31]
We found that TM-25659 treatment significantly resulted in increased TAZ protein in the nuclear fraction while it resulted in decreased TAZ in the cytoplasmic compartment in both ADSCs and Bone mesenchymal stem cell (BMSC)
Summary
Adipose-derived stem cells (ADSCs) are an attractive cell source for bone tissue engineering and have great potential for bone regeneration and defect repair. Mounting evidence has established that ADSCs hold significant promise for regenerative therapies largely due to their convenient isolation, abundant sources, lack of immunogenicity, and minor donor morbidity [5, 6]. To achieve their therapeutic potential and utility depends on the understanding of the molecular mechanisms driving their differentiation [7]. Stem cell differentiation biased by a pharmacological or chemical approach using small molecules appears to a novel and favorable way to promote regeneration with superior translational potentials which might circumvent limitations of genetic manipulation and ethical concerns [12, 14]
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