Pluripotent Stem Cells and Skeletal Regeneration—Promise and Potential

Wu, Joy Y.

doi:10.1007/s11914-015-0285-9

Cited by 12 publications

(13 citation statements)

References 90 publications

(94 reference statements)

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“…A typical protocol to direct the differentiation of mouse or human ESCs into osteoblasts involves formation of embryoid bodies (EBs) that are subsequently disaggregated and plated in osteogenic medium containing ascorbic acid and β‐glycerophosphate (reviewed in ref. ). The addition of factors such as dexamethasone, retinoic acid, bone morphogenetic proteins, and vitamin D3 as well as the use of three‐dimensional scaffolds have been reported to enhance osteogenic differentiation.…”

Section: Introductionmentioning

confidence: 97%

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In Vivo Rescue of the Hematopoietic Niche By Pluripotent Stem Cell Complementation of Defective Osteoblast Compartments

Chubb

Riley

et al. 2017

Stem Cells

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Bone-forming osteoblasts play critical roles in supporting bone marrow hematopoiesis. Pluripotent stem cells (PSCs), including embryonic stem (ES) cells and induced pluripotent stem (iPS) cells, are capable of differentiating into osteoblasts. To determine the capacity of stem cells needed to rescue aberrant skeletal development and bone marrow hematopoiesis in vivo, we employed a skeletal complementation model. Mice deficient in Runx2, a master transcription factor for osteoblastogenesis, fail to form a mineralized skeleton and bone marrow. Wild-type GFP+ ES and YFP+ iPS cells were introduced into Runx2-null blastocyst-stage embryos. We assessed GFP/YFP+ cell contribution by whole-mount fluorescence and histological analysis and found that the proportion of PSCs in the resulting chimeric embryos is directly correlated with the degree of mineralization in the skull. Moreover, PSC contribution to long bones successfully restored bone marrow hematopoiesis. We validated this finding in a separate model with diphtheria toxin A-mediated ablation of hypertrophic chondrocytes and osteoblasts. Remarkably, chimeric embryos harboring as little as 37.5% wild-type PSCs revealed grossly normal skeletal morphology, suggesting a near-complete rescue of skeletogenesis. In summary, we demonstrate that fractional contribution of PSCs in vivo is sufficient to complement and reconstitute an osteoblast-deficient skeleton and hematopoietic marrow. Further investigation using genetically modified PSCs with conditional loss of gene function in osteoblasts will enable us to address the specific roles of signaling mediators to regulate bone formation and hematopoietic niches in vivo.

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Section: Introductionmentioning

confidence: 97%

“…As with ESCs, both mouse and human iPSCs have been differentiated into osteoblasts using similar protocols (reviewed in ref. [ ]). More recently, Kanke et al have differentiated iPSCs into osteoblasts in a monolayer culture without EB formation via mesodermal intermediates using small molecule inhibitors .…”

Section: Introductionmentioning

confidence: 99%

In Vivo Rescue of the Hematopoietic Niche By Pluripotent Stem Cell Complementation of Defective Osteoblast Compartments

Chubb

Riley

et al. 2017

Stem Cells

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“…However, since in vivo transplantation of ESCs and iPSCs carries the risk of teratoma formation, osteoblasts derived from ESC and iPSC differentiation in vitro might be preferred for bone tissue engineering purposes. Several recent studies have focused on differentiating both ESCs and iPSCs into osteoblasts [8][9][10]. ESCs and iPSCs can be differentiated to the osteoblast lineage by first forming embryoid bodies (EBs), in which mesoderm lineage cells differentiate to osteoblast lineage cells under osteogenic factors including ascorbic acid, ßglycerophosphate, and dexamethasone [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27].…”

Section: Introductionmentioning

confidence: 99%

Pluripotent stem cells as a source of osteoblasts for bone tissue regeneration

et al. 2019

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Appropriate and abundant sources of bone-forming osteoblasts are essential for bone tissue engineering. Pluripotent stem cells can self-renew and thereby offer a potentially unlimited supply of osteoblasts, a significant advantage over other cell sources. We generated mouse embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) from transgenic mice expressing rat 2.3 kb type I collagen promoter-driven green fluorescent protein (Col2.3GFP), a reporter of the osteoblast lineage. We demonstrated that Col2.3GFP ESCs and iPSCs can be successfully differentiated to osteoblast lineage cells that express Col2.3GFP in vitro. We harvested GFP osteoblasts differentiated from ESCs. Genome wide gene expression profiles validated that ESC- and iPSC-derived osteoblasts resemble calvarial osteoblasts, and that Col2.3GFP expression serves as a marker for mature osteoblasts. Our results confirm the cell identity of ESC- and iPSC-derived osteoblasts and highlight the potential of pluripotent stem cells as a source of osteoblasts for regenerative medicine.

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“…Cells of the osteoblast lineage are also important for the support of bone marrow hematopoiesis and immune cell development . Therefore, the ability to efficiently and reliably generate patient‐specific osteoblasts would have great clinical implications for the treatment of bone defects and diseases …”

Section: Introductionmentioning

confidence: 99%

“…Osteoblasts are derived from bone marrow mesenchymal stem cells (MSCs) . MSCs harvested from bone marrow stromal cells, as well as pluripotent stem cells including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), have been used as sources of osteoblasts and demonstrate osteogenic potential in vitro and/or in vivo . However, mesenchymal stromal cells gradually lose their multipotency and are limited by large donor variation, while ESCs and iPSCs are limited by low osteogenic differentiation efficiency and the risk of teratoma formation .…”

Section: Introductionmentioning

confidence: 99%

Direct Reprogramming of Mouse Fibroblasts into Functional Osteoblasts

Zhu

Swami

Yang

et al. 2019

Journal of Bone and Mineral Research

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Although induced pluripotent stem cells hold promise as a potential source of osteoblasts for skeletal regeneration, the induction of pluripotency followed by directed differentiation into osteoblasts is time consuming and low yield. In contrast, direct lineage reprogramming without an intervening stem/progenitor cell stage would be a more efficient approach to generate osteoblasts. We screened combinations of osteogenic transcription factors and identified four factors, Runx2, Osx, Dlx5, and ATF4, that rapidly and efficiently reprogram mouse fibroblasts derived from 2.3 kb type I collagen promoter‐driven green fluorescent protein (Col2.3GFP) transgenic mice into induced osteoblast cells (iOBs). iOBs exhibit osteoblast morphology, form mineralized nodules, and express Col2.3GFP and gene markers of osteoblast differentiation. The global transcriptome profiles validated that iOBs resemble primary osteoblasts. Genomewide DNA methylation analysis demonstrates that within differentially methylated loci, the methylation status of iOBs more closely resembles primary osteoblasts than mouse fibroblasts. We further demonstrate that Col2.3GFP+ iOBs have transcriptome profiles similar to GFP+ cells harvested from Col2.3GFP mouse bone chips. Functionally, Col2.3GFP+ iOBs form mineralized bone structures after subcutaneous implantation in immunodeficient mice and contribute to bone healing in a tibia bone fracture model. These findings provide an approach to derive and study osteoblasts for skeletal regeneration. © 2019 American Society for Bone and Mineral Research.

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Pluripotent Stem Cells and Skeletal Regeneration—Promise and Potential

Cited by 12 publications

References 90 publications

In Vivo Rescue of the Hematopoietic Niche By Pluripotent Stem Cell Complementation of Defective Osteoblast Compartments

In Vivo Rescue of the Hematopoietic Niche By Pluripotent Stem Cell Complementation of Defective Osteoblast Compartments

Pluripotent stem cells as a source of osteoblasts for bone tissue regeneration

Direct Reprogramming of Mouse Fibroblasts into Functional Osteoblasts

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