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Lineage-specific differentiation of osteogenic progenitors from pluripotent stem cells reveals the FGF1-RUNX2 association in neural crest-derived osteoprogenitors.

ABSTRACT: Human pluripotent stem cells (hPSCs) can provide a platform to model bone organogenesis and disease. To reflect the developmental process of the human skeleton, hPSC differentiation methods should include osteogenic progenitors (OPs) arising from three distinct embryonic lineages: the paraxial mesoderm, lateral plate mesoderm, and neural crest. Although OP differentiation protocols have been developed, the lineage from which they are derived, as well as characterization of their genetic and molecular differences, has not been well reported. Therefore, to generate lineage-specific OPs from human embryonic stem cells and human induced pluripotent stem cells, we employed stepwise differentiation of paraxial mesoderm-like cells, lateral plate mesoderm-like cells, and neural crest-like cells toward their respective OP subpopulation. Successful differentiation, confirmed through gene expression and in vivo assays, permitted the identification of transcriptomic signatures of all three cell populations. We also report, for the first time, high FGF1 levels in neural crest-derived OPs-a notable finding given the critical role of fibroblast growth factors (FGFs) in osteogenesis and mineral homeostasis. Our results indicate that FGF1 influences RUNX2 levels, with concomitant changes in ERK1/2 signaling. Overall, our study further validates hPSCs' power to model bone development and disease and reveals new, potentially important pathways influencing these processes.

SUBMITTER: Kidwai F

PROVIDER: S-EPMC7484058 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Intermediate progenitor populations play a crucial role in the regional specification and differentiation of the cranial neural crest. On the basis of global gene expression profiles, gene cohort expression levels, and epigenetic modifications, we have defined key factors involved in the differentiation of dental follicle (DF) intermediate progenitors into periodontal lineages, including alveolar bone (AB) osteoblasts, cementoblasts, and periodontal ligament (PDL) cells. When comparing differentially expressed genes, PDL cells most closely resembled DF progenitors, followed by AB osteoblasts and cementoblasts as the most distant population. According to gene ontology analyses, extracellular matrix-adhesion proteins were substantially increased in PDL cells, osteogenesis factors were elevated in AB osteoblasts, and gene expression levels were lower in cementoblasts, especially in the cytokine group. Unique signature proteins included interleukin 6, paired-like homeodomain transcription factor 2, thrombospondin 2, and glial cell line-derived neurotrophic factor for DF progenitors; asporin and prostaglandin-H2 D-isomerase for AB osteoblasts; and keratin 18, Netrin 4, Jagged 1, and Dickkopf1 for cementoblasts, as verified by western blot analysis. Secreted frizzled-related protein 1 was preferentially expressed in PDL cells, whereas matrix Gla-protein, bone sialoprotein, and insulin-like growth factor binding protein 5 were higher in AB osteoblasts than in cementoblasts. On an epigenetic level, DF progenitors featured high levels of the euchromatin marker H3K4me3, whereas PDL cells, AB osteoblasts, and cementoblasts contained high levels of the transcriptional repressor H3K9me3. Together, our data indicate that in addition to changes in signature gene expression, unique shifts in gene cohort expression levels, epigenetic modifications, and changes in cell morphology contribute to the individuation of tissue populations from a common neural-crest-derived ancestor.

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Lineage-specific differentiation of osteogenic progenitors from pluripotent stem cells reveals the FGF1-RUNX2 association in neural crest-derived osteoprogenitors.

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