Embryonic origin and Hox status determine progenitor cell fate during adult bone regeneration

Abstract

The fetal skeleton arises from neural crest and from mesoderm. Here, we provide evidence that each lineage contributes a unique stem cell population to the regeneration of injured adult bones. Using Wnt1Cre::Z/EG mice we found that the neural crest-derived mandible heals with neural crest-derived skeletal stem cells, whereas the mesoderm-derived tibia heals with mesoderm-derived stem cells. We tested whether skeletal stem cells from each lineage were functionally interchangeable by grafting mesodermderived cells into mandibular defects, and vice versa. All of the grafting scenarios, except one, healed through the direct differentiation of skeletal stem cells into osteoblasts; when mesoderm-derived cells were transplanted into tibial defects they differentiated into osteoblasts but when transplanted into mandibular defects they differentiated into chondrocytes. A mismatch between the Hox gene expression status of the host and donor cells might be responsible for this aberration in bone repair. We found that initially, mandibular skeletal progenitor cells are Hox-negative but that they adopt a Hoxa11-positive profile when transplanted into a tibial defect. Conversely, tibial skeletal progenitor cells are Hox-positive and maintain this Hox status even when transplanted into a Hox-negative mandibular defect. Skeletal progenitor cells from the two lineages also show differences in osteogenic potential and proliferation, which translate into more robust in vivo bone regeneration by neural crest-derived cells. Thus, embryonic origin and Hox gene expression status distinguish neural crest-derived from mesoderm-derived skeletal progenitor cells, and both characteristics influence the process of adult bone regeneration.

Investigation of orofacial stem cell niches and their innervation through microfluidic devices

“…Microfluidics for analysing stem cell niches area (Giuliani et al, 2013;Huang et al, 2009;Leucht et al, 2008;La Noce et al, 2014). It has been shown that the embryonic origin of stem cells, combined with their Hox expression profile, play a key role in determining their fate during bone regeneration (Leucht et al, 2008).…”

“…It has been shown that the embryonic origin of stem cells, combined with their Hox expression profile, play a key role in determining their fate during bone regeneration (Leucht et al, 2008). Indeed, Hox-negative cranial neural crest-derived stem cells adopt a Hox-positive profile and differentiate into osteoblasts after transplantation into the tibia.…”

“…However, BMSCs cells do not have the same embryonic origin as the cells forming the orofacial tissues. Moreover, numerous studies reported that BMSCs differ from MSCs isolated from the orofacial 216 www.ecmjournal.org P Pagella et alMicrofluidics for analysing stem cell niches area (Giuliani et al, 2013;Huang et al, 2009;Leucht et al, 2008;La Noce et al, 2014). It has been shown that the embryonic origin of stem cells, combined with their Hox expression profile, play a key role in determining their fate during bone regeneration (Leucht et al, 2008).…”

“…Indeed, Hox-negative cranial neural crest-derived stem cells adopt a Hox-positive profile and differentiate into osteoblasts after transplantation into the tibia. In contrast, Hox-positive mesoderm-derived stem cells are not able to adopt a Hox-negative profile and differentiate into chondroblasts after transplantation into the mandible (Leucht et al, 2008). These results indicate that stem cell plasticity depends of the embryonic origin of the cells that retain their "positional memory" (Grapin-Botton et al, 1995).…”

Novel Adult Stem Cells for Peripheral Nerve Regeneration

“…Transgenic mice, expressing Cre recombinase under the control of the Wnt1 promoter were mated with Rosa26-LoxPLacZ mice to generate Wnt1-Cre/LoxP-LacZ mice. Genotyping was performed with PCR using total DNA extracted from mice tail tissues, as described previously 30,31,55 . The sequences of primers used for genotyping were shown in Supplementary Table S4.…”