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Osteoblast Differentiation Study Recommends Choosing your Stem Cell Wisely!

Review of “Low osteogenic yield in human pluripotent stem cells associates with differential neural crest promoter methylation” from STEM CELLS by Stuart P. Atkinson

The application of bone-forming osteoblasts differentiated from human induced pluripotent stem cells (hiPSCs) promises a patient-specific means to replace diseased or injured bone tissue. Recent research from the group of Nicole I. zur Nieden (University of California Riverside, USA) has focused on a side-by-side assessment of iPSC-derived and human embryonic stem cell (hESC)-derived osteoblasts to compare both the differentiation efficiency and the differentiation route taken during the process. Studies have demonstrated that osteoblasts that originate from the neural crest display superior grafting abilities when compared to cells arising from the mesodermal lineage [1, 2]. Now, the team´s new STEM CELLS study establishes that DNA methylation analysis of specific genes may point to the optimal source of cells for applications in regenerative therapies [3].

Sparks et al. compared hiPSC lines (RIV4 and 9) generated by the retroviral integration of OCT4, KLF4, and SOX2 into foreskin fibroblasts and the widely used H9 hESC line with regards to their ability to form osteoblasts following induction by 1α,25 dihydroxy vitamin D3 (VD3) treatment [4]. Interestingly, the authors discovered that both hiPSC lines formed osteoblasts with lower levels of bone‐specific mRNA expression (e.g., osteocalcin (OCN)) and calcium accumulation.

In-depth analyses of the differentiation routes utilized by each cell line suggested that hESCs differentiated into osteoblasts through a neural crest cell intermediary while the hiPSCs mainly differentiated through via the mesodermal lineage. However, the authors did not link differentiation efficiency and the preferred differentiation route to cell type (either hESC or hiPSC), but instead uncovered a correlation to the levels of DNA methylation present at the promoters of crucial neural crest genes, such as PAX7 and TWIST1. While H9 cells exhibited hypomethylated neural crest gene promoters and neural crest gene expression, the same sequences displayed hypermethylation and lower gene expression levels in the hiPSC lines assessed.

The take-home message from this “comparatively” exciting study is that each pluripotent stem cell line will display inherent differences in osteoblast producing potential, although we can now choose the optimal cell line based on DNA methylation analysis of select neural crest genes. 

Will this provide a much-needed boost for stem cells strategies to replace diseased or injured bone tissue? Stay tuned to the Stem Cells Portal to find out!


  1. Jheon AH and Schneider RA, The cells that fill the bill: neural crest and the evolution of craniofacial development. J Dent Res 2009;88:12-21.
  2. Park S and Im GI, Embryonic stem cells and induced pluripotent stem cells for skeletal regeneration. Tissue Eng Part B Rev 2014;20:381-91.
  3. Sparks NRL, Martinez IKC, Soto CH, et al., Low Osteogenic Yield in Human Pluripotent Stem Cells Associates with Differential Neural Crest Promoter Methylation. STEM CELLS 2018;36:349-362.
  4. Ding H, Keller KC, Martinez IK, et al., NO-beta-catenin crosstalk modulates primitive streak formation prior to embryonic stem cell osteogenic differentiation. J Cell Sci 2012;125:5564-77.