Dissecting human embryonic skeletal stem cell ontogeny by single-cell transcriptomic and functional analyses
Open Access
- 20 January 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Research
- Vol. 31 (7), 742-757
- https://doi.org/10.1038/s41422-021-00467-z
Abstract
Human skeletal stem cells (SSCs) have been discovered in fetal and adult long bones. However, the spatiotemporal ontogeny of human embryonic SSCs during early skeletogenesis remains elusive. Here we map the transcriptional landscape of human limb buds and embryonic long bones at single-cell resolution to address this fundamental question. We found remarkable heterogeneity within human limb bud mesenchyme and epithelium, and aligned them along the proximal–distal and anterior–posterior axes using known marker genes. Osteo-chondrogenic progenitors first appeared in the core limb bud mesenchyme, which give rise to multiple populations of stem/progenitor cells in embryonic long bones undergoing endochondral ossification. Importantly, a perichondrial embryonic skeletal stem/progenitor cell (eSSPC) subset was identified, which could self-renew and generate the osteochondral lineage cells, but not adipocytes or hematopoietic stroma. eSSPCs are marked by the adhesion molecule CADM1 and highly enriched with FOXP1/2 transcriptional network. Interestingly, neural crest-derived cells with similar phenotypic markers and transcriptional networks were also found in the sagittal suture of human embryonic calvaria. Taken together, this study revealed the cellular heterogeneity and lineage hierarchy during human embryonic skeletogenesis, and identified distinct skeletal stem/progenitor cells that orchestrate endochondral and intramembranous ossification.Keywords
This publication has 108 references indexed in Scilit:
- Endothelial and perivascular cells maintain haematopoietic stem cellsNature, 2012
- Neural crest stem cells: discovery, properties and potential for therapyCell Research, 2012
- Osteoblast Precursors, but Not Mature Osteoblasts, Move into Developing and Fractured Bones along with Invading Blood VesselsDevelopmental Cell, 2010
- Vertebrate SkeletogenesisCurrent Topics in Developmental Biology, 2010
- Sox10 is required for Schwann cell identity and progression beyond the immature Schwann cell stageThe Journal of cell biology, 2010
- Endochondral ossification is required for haematopoietic stem-cell niche formationNature, 2008
- Genetic evidence that FGFs have an instructive role in limb proximal–distal patterningNature, 2008
- A cellular lineage analysis of the chick limb budDevelopmental Biology, 2007
- Developmental regulation of the growth plateNature, 2003
- Muscle deficiency and neonatal death in mice with a targeted mutation in the myogenin geneNature, 1993