Human growth plates house resting zone sub-populations with features of quiescent stem cells

Abstract

Maintaining postnatal bone growth is crucial for humans to reach their final height. To determine transcriptional networks coordinating this process, we applied spatially resolved transcriptomics to growth plate biopsies obtained from healthy adolescents who underwent epiphysiodesis surgery for idiopathic tall stature. Spatial profiling revealed new markers for each zone of the human growth plate and identified genes associated with poorly understood growth disorders, including the novel hypertrophic zone marker SGMS2. We elaborated on this finding and established that Sgms2 is present in growth plate-derived matrix vesicles, and its activity facilitates mineralization - a process impaired in patients with SGMS2 mutations. By exploring the low transcriptional activity of resting zone chondrocytes, we found that a subset of these cells exists in a functionally quiescent state in vivo, as determined by their predominantly nuclear mRNA, abundant heterochromatin, and ability to exit the G0 phase under specific conditions - features shared with skeletal stem cells in mouse growth plates. Additionally, we identified distinct sub-populations of human resting zone chondrocytes; an exploration of their hierarchy determined that CHRDL2 and/or SFRP5-positive sub-populations were among the least quiescent resting zone cells. In summary, we generated a comprehensive map of gene expression within the human growth plate, revealing novel zone-specific markers, new primary growth disorders, candidate pharmacological targets, and sub-populations of resting zone chondrocytes with features of quiescent stem cells. These results contribute to a better understanding of the cellular and molecular mechanisms governing human height and can facilitate improved diagnosis and treatment strategies for patients with skeletal growth disorders.

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Funding

Vetenskapsrådet (Swedish Research Council)(2019-01919)

Novo Nordisk Fonden (Novo Nordisk Foundation)(0067241)

Stiftelsen Syskonen Svenssons Stiftelse för Medicinsk Forskning(-)

Karolinska Institutet (Karolinska Institute)(-)

Ministry of Economy and Competitiveness | Instituto de Salud Carlos III (Institute of Health Carlos III)

EC | European Regional Development Fund (Europski Fond za Regionalni Razvoj)(PI20/01308, PI23/00516)

Cancer Research UK (CRUK)(C355/A26819)

King Abdullah University of Science and Technology (KAUST)(BAS/1/1078-01-01)

EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)(101021019)

Stiftelsen för Strategisk Forskning (Swedish Foundation for Strategic Research)(SB16-0014)

Science for Life Laboratory (SciLifeLab)

RIGHTS & PERMISSIONS

The Author(s)