Activating PIK3CA mutation promotes osteogenesis of bone marrow mesenchymal stem cells in macrodactyly.
Hengqing CuiGang HanBin SunXia FangXinyi DaiShengbo ZhouHailei MaoBin WangPublished in: Cell death & disease (2020)
Macrodactyly is a disabling congenital disease characterized by overgrowth of soft tissues and bones, which leads to finger enlargement and joint deformity. The mechanism of bone overgrowth in macrodactyly was rarely understood. In our study bone manifestations of three macrodactyly patients were analyzed by micro-CT. PIK3CA mutation was detected by next-generation sequencing (NGS) of a tumor gene-panel. The PI3K/AKT/mTOR pathway activation and target genes were analyzed. The osteogenic potential of macrodactyly-derived bone marrow mesenchymal stem cells (MAC-BMSCs) was compared with polydactyly-derived bone marrow mesenchymal stem cells (PD-BMSCs). PIK3CA inhibitors were tested for proliferation and osteogenesis potential of MAC-BMSCs. Activating PIK3CA mutations and activation of PI3K/AKT/mTOR pathway were detected in all MAC-BMSCs. MAC-BMSCs had enhanced osteogenesis potential compared with PD-BMSCs. PIK3CA knockdown by shRNA or BYL719 treatment significantly reduced osteogenic differentiation capacity of MAC-BMSCs. RNA-Seq and qRT-PCR revealed the upregulation of distal-less homeobox 5 (DLX5) in MAC-BMSCs compared with PD-BMSCs. The osteogenic potential of MAC-BMSCs was inhibited by DLX5 knockdown, indicating that DLX5 is a downstream target of PIK3CA activation-mediated osteogenesis. This study revealed that osteogenic differentiation in MAC-BMSCs is enhanced by PIK3CA activation mutation through PI3K/AKT/mTOR signaling pathway and can be reversed by PIK3CA knockdown or drug inhibition.
Keyphrases
- signaling pathway
- mesenchymal stem cells
- rna seq
- single cell
- bone marrow
- protein kinase
- bone regeneration
- gene expression
- genome wide
- end stage renal disease
- magnetic resonance imaging
- human health
- pi k akt
- computed tomography
- cell proliferation
- chronic kidney disease
- oxidative stress
- newly diagnosed
- climate change
- poor prognosis
- prognostic factors
- dna methylation
- magnetic resonance
- transcription factor
- long non coding rna
- bone loss
- adverse drug
- patient reported outcomes
- combination therapy
- patient reported