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Transdifferentition of Fibroblasts into Osteoblasts Provides Boost for Bone Tissue Engineering

Review of “Reprogramming of human fibroblasts into osteoblasts by insulin-like growth factor-binding protein 7” from STEM CELLS Translational Medicine by Stuart P. Atkinson

The transplantation of various somatic cell types differentiated from human induced pluripotent stem cells (hiPSCs) carries the risk that “left-over” undifferentiated iPSCs may possess tumor-forming abilities [1]. The chemical induction of direct reprogramming (or trans-differentiation) of one somatic cell into another bypasses the need for the iPSC stage; therefore, somatic cells generated in this manner may possess greater clinical potential. 

In a recent STEM CELLS Translational Medicine article [2], researchers led by Zufu Lu and Hala Zreiqat (University of Sydney, NSW, Australia) described their attempts to transdifferentiate fibroblasts into osteoblasts, given their generally similar gene expression profiles when studied in vitro, through the study of osteoblast secreted factors. Fascinatingly, the authors now report that exogenous insulin‐like growth factor binding protein‐7 (IGFBP7), previously shown to be in bone diseases and osteogenic differentiation of mesenchymal stem cells [3, 4], has the ability to trans-differentiate fibroblasts into osteoblasts that can form ectopic bone.

Lu et al. initially discovered that exposure to growth medium conditioned by human osteoblasts could induce the transdifferentiation of human fibroblasts into functional osteoblasts and analysis of the proteomic profile of the osteoblast-conditioned media revealed elevated levels of IGFBP7 protein. With this knowledge in mind, the authors sought to attempt reprogramming with recombinant IGFBP7, finding that induced senescence and autocrine IL‐6 signaling mediated a phenotypic switch from fibroblasts to osteoblasts in vitro and prompted the expression of osteoblastic marker genes. Of note, the exposure of fibroblast to BMP2 bone inductive protein failed to elevate osteogenic gene expression levels significantly. Encouragingly, while fibroblasts exposed to osteoblast-conditioned medium failed to display any in vivo bone-forming potential, IGFBP7-treated fibroblasts also possessed the ability to produce mineralized tissue in a mouse xenograft model of ectopic bone formation

While the authors hope that exposure of fibroblasts to IGFBP7 may lead to the development of simple and effective bone tissue engineering strategies, they do note the need to generate a complete overview of the transcriptomic profile of fibroblasts undergoing reprogramming and to optimize the ex-vivo transdifferentiation of fibroblasts into osteoblasts further.

For more on transdifferentiation and novel bone tissue engineering strategies, stay tuned to the Stem Cells Portal!

References

  1. Assou S, Bouckenheimer J, and De Vos J, Concise Review: Assessing the Genome Integrity of Human Induced Pluripotent Stem Cells: What Quality Control Metrics? STEM CELLS 2018;36:814-821.
  2. Lu Z, Chiu J, Lee LR, et al., Reprogramming of human fibroblasts into osteoblasts by insulin-like growth factor-binding protein 7. STEM CELLS Translational Medicine 2020;9:403-415.
  3. Zhang W, Chen E, Chen M, et al., IGFBP7 regulates the osteogenic differentiation of bone marrow-derived mesenchymal stem cells via Wnt/beta-catenin signaling pathway. FASEB J 2018;32:2280-2291.
  4. Infante A and Rodriguez CI, Secretome analysis of in vitro aged human mesenchymal stem cells reveals IGFBP7 as a putative factor for promoting osteogenesis. Sci Rep 2018;8:4632.