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Lineage Tracing Describes how Chondroprogenitors Control Bone Elongation

Review of “A radical switch in clonality reveals a stem cell niche in the epiphyseal growth plate” from Nature by Stuart P. Atkinson

The growth plates present at each end of long bones in children and adolescents are narrow discs of cartilage that provide a continuous supply of chondrocytes for endochondral ossification, one of the two essential processes which sustain lengthwise bone growth [1]. While studies have suggested that chondroprogenitors residing in the resting layer of the growth plates supply cells for longitudinal growth and become depleted over time, this model remains unverified. 

However, a team of researchers from the laboratories of Phillip T. Newton and Andrei S. Chagin at Karolinska University (Stockholm, Sweden) have now discovered that a stem cell niche within the growth plate develops postnatally, facilitating the self-renewal of chondrocyte progenitors and providing a continuous supply of chondrocytes over a prolonged period for bone elongation [2]. Overall, the authors believe that their new findings may help to develop new and improved therapeutic approaches for children with growth disorders.

Through clonal genetic tracing of chondrogenic lineage cells in crossed transgenic mice [3, 4], the authors discovered that initial periods of bone elongation (during fetal and neonatal periods) involved the continuous recruitment and depletion of various chondroprogenitors for the production of multiclonal chondrocytes for bone formation. 

After the growth plate forms, the remaining chondroprogenitors self-renew and amplify following the formation of the secondary ossification center at the growth plate, which acts as a stem cell niche. This mechanism permits a fraction of the large number of chondroprogenitors to asymmetrically divide to generate large, stable monoclonal columns of chondrocytes for the required bone elongation in juveniles. Interestingly, the authors discovered that the regulation of this secondary pool of chondroprogenitors required the concerted activities of the hedgehog and mammalian target of rapamycin complex 1 signaling pathways, thereby providing potential targets for small molecule modulators to control bone growth.

The authors note that the formation of a nice for of slowly dividing stem/progenitor cells appears to represent a common mechanism at play in tissues that require the ongoing generation of terminally-differentiated cell progeny [5]. Furthermore, they also highlight the potential utility of these findings to researchers searching for treatment approaches for children suffering from several types of growth disorders.

For more on chondroprogenitors, bone development and more, stay tuned to the Stem Cells Portal!

References

  1. Hall BK, in Bones and Cartilage (Second Edition), B.K. Hall, Editor. 2015, Academic Press: San Diego.
  2. Newton PT, Li L, Zhou B, et al., A radical switch in clonality reveals a stem cell niche in the epiphyseal growth plate. Nature 2019;567:234-238.
  3. Nakamura E, Nguyen MT, and Mackem S, Kinetics of tamoxifen-regulated Cre activity in mice using a cartilage-specific CreER(T) to assay temporal activity windows along the proximodistal limb skeleton. Developmental Dynamics 2006;235:2603-12.
  4. Snippert HJ, van der Flier LG, Sato T, et al., Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. Cell 2010;143:134-44.
  5. Morrison SJ and Spradling AC, Stem cells and niches: mechanisms that promote stem cell maintenance throughout life. Cell 2008;132:598-611.