# Gli1-expressing stromal cells are highly reparative precursors of long-lived chondroprogenitors in the fetal murine limb

## TL;DR

This study identifies Gli1+ fetal cells as precursors to long-lived cartilage progenitors in long bones, which can compensate for growth disruptions.

## Contribution

The paper reveals that Gli1+ cells originate from Pdgfra+ cells and act as reparative precursors in cartilage development.

## Key findings

- Gli1+ cells are fetal precursors of postnatal long-lived cartilage progenitors.
- Gli1+ cells remain dormant until postnatal stages but expand in response to developmental perturbations.
- Reparative Gli1+ cells originate from Pdgfra+ cells outside the cartilage.

## Abstract

The growth-plate cartilage of the developing long bones is a well-known system of spatially segregated stem/progenitor, transient amplifying and terminally differentiated cells. However, the regulation of the number and activity of long-lived cartilage progenitors (LLCPs) is poorly understood, despite its relevance for understanding human-height variation, the evolution of limb size and proportions and the aetiology of skeletal growth disorders. Moreover, whether their behaviour can adapt to developmental perturbations, generating robustness, has not been explored. Here, we show that Gli1+ cells are the fetal precursors of postnatal LLCPs, and that Gli1+ LLCP precursors remain mostly dormant until postnatal stages. However, in response to genetically-induced cell-cycle arrest targeted to the fetal cartilage, they expand in the cartilage, enabling normal growth. We further show that reparative Gli1+ cells originate from Pdgfra+ cells outside the cartilage, revealing the surrounding tissues as an unexpected CP source. Elucidating how stromal cells become Gli1+ LLCPs could shed light on developmental robustness and lead to growth-boosting therapies.

Qu, Razmara et al. show that Gli1+ fetal cells give rise to long-lived cartilage progenitors in the long bones. While normally dormant until postnatally, they expand upon (and compensate for) growth perturbations, arising from external Pdgfra+ cells.