A transcriptional atlas of the pubertal human growth plate reveals direct stimulation of cartilage stem cells by growth hormone

The cartilaginous growth plate is a critical organ responsible for longitudinal bone growth. It remains open throughout life in mice but closes in humans after puberty. Growth hormone (GH) is a widely used therapy for children with growth retardation and open growth plates. However, it remains unclear whether GH directly targets human growth plates. Furthermore, while cartilage stem cells have recently been identified in mouse growth plates, their presence and GH responsiveness in human growth plates are unknown. To address these gaps, we characterized the cellular and molecular organization of early pubertal human growth plates using unique tissue samples obtained during growth-restricting surgeries. Our analysis identified two distinct populations of stem cells differing in cycling activity, molecular profiles, and regulatory factors. Quiescent stem cells were localized within a niche characterized by low Wnt and TGFβ signaling. To investigate the direct effects of GH, we developed a human growth plate explant culture system. GH directly stimulated explant growth and promoted stem cell proliferation by activating the JAK/STAT, TGFβ, and ERK pathways while inhibiting the AKT pathway. Notably, activation of the TGFβ pathway occurred in an autocrine manner. These findings provide critical new insights into human longitudinal growth and the mechanisms of GH action, with potential implications for optimizing treatments for growth disorders.