Abstract
The generation of functional osteoblasts from human somatic cells could provide an alternative means of regenerative therapy for bone disorders such as osteoporosis. In this study, we demonstrated the direct phenotypic conversion of human dermal fibroblasts (HDFs) into osteoblasts by culturing them in osteogenic medium supplemented with valproic acid (VPA), a histone deacetylase (HDAC) inhibitor. HDFs cultured with the VPA in osteogenic medium exhibited expression of alkaline phosphatase and deposition of mineralized calcium matrices, which are phenotypical characteristics of functional osteoblasts. They also expressed osteoblast-specific genes such as alkaline phosphatase, osteopontin, and bone sialoprotein, which demonstrated their direct conversion into osteoblasts. In addition, co-treatment with VPA and a specific inhibitor for activin-like kinase 5 (ALK5i II) had a synergistic effect on direct conversion. It is considered that the inductive effect of VPA on the conversion into osteoblast-lineage is due to the opening of the nucleosome structure by HDAC inhibitor, which facilitates chromatin remodeling and cellular reprogramming. Our findings provide a novel insight into the direct conversion of human somatic cells into transgene-free osteoblasts with small chemical compounds, thus making bone regeneration using cellular reprogramming strategy more clinically feasible.
Highlights
Transcription factors are proteins that can control the transcriptional regulation of genetic information by binding to specific DNA sequences [1,2]
In 2006 and 2007, ground-breaking research by Takahashi and Yamanaka demonstrated that forced expression of a set of transcription factors such as c-Myc, Oct3/4, Sox2, and Klf-4, enable reprogramming of somatic cells into induced pluripotent stem cells that have the ability to self-renew and pluripotency [3,4]
Some small chemicals have been shown to enhance the differentiation of stem cells to other lineages [20,21,22,23,24], some increase the reprogramming and induction of stem cell phenotypes [25,26,27,28,29], while others promote the direct conversion of somatic cells into other lineages [30,31,32]
Summary
Transcription factors ( known as reprogramming factors) are proteins that can control the transcriptional regulation of genetic information by binding to specific DNA sequences [1,2]. In 2006 and 2007, ground-breaking research by Takahashi and Yamanaka demonstrated that forced expression of a set of transcription factors such as c-Myc, Oct3/4, Sox, and Klf-4, enable reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) that have the ability to self-renew and pluripotency [3,4]. Numerous studies have been conducted to reprogram and convert somatic cells into targeted phenotypes by using various approaches including genetic manipulation, biomaterials, growth factors, small molecules, and cocktails thereof. The “direct conversion” ( known as direct reprogramming) of somatic cells to another differentiated lineage by introducing a combination of transcription factors, is considered to be a more promising strategy, and it involves bypassing the intermediate pluripotent stage [5].
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