Type II collagen-positive progenitors are major stem cells to control skeleton development and vascular formation

Abstract

Previous studies have revealed that type II collagen positive (Col2+) cells represent a kind of skeleton stem cells (SSC) and their descendants contribute to chondrocytes, osteoblasts, Cxcl12 (chemokine (C-X-C motif) ligand 12)-abundant stromal cells and bone marrow stromal/mesenchymal progenitor cells in postnatal life. To further elucidate the function of Col2+ progenitors, we generated mice with ablation of either embryonic or postnatal Col2+ cells. Embryonic ablation of Col2+ progenitors caused the mouse die at newborn with the absence of all skeleton except partial craniofacial bone, as well as multiple organ development defects and blood vessel loss. Postnatal ablation of Col2+ cells causes mouse growth retardation and collagenopathy phenotype. By examining Col2+ cells ablated mice, we found that, besides contributing to long bone and vertebral bone development, Col2+ cells are also involved in calvaria bone development. Meanwhile, Col2+ cells are the major cells to contribute all skeletal development including spine, rib and long bones. Moreover, our functional study provide evidence that intramembranous ossification is involved in craniofacial bone formation and long bone development, but not participates in spine development. By performing lineage tracing experiments in embryonic or postnatal mice, we discovered that the presence of Col2+ progenitors not only within the bone marrow and growth plate (GP) but also within articular cartilage. Moreover, the number and differentiation ability of Col2+ progenitors were decreased with age in long bone and knee. Furthermore, fate-mapping studies revealed that Col2+ progenitors also contributed to CD31+ blood vessel endothelial development in calvariae bone, long bone and many organs. Interestingly, we found only 25.4% CD31+ blood vessel endothelial in long bone but almost all the CD31+ blood vessel endothelial in calvariae bone are differentiated from Col2+ cells. Consistently, postnatal Col2+ cells differentiated to both chondrocytes and CD31+ blood vessel endothelial cells during bone fracture healing. Therefore, this study reveals that Col2+ progenitors are the major source of endochondral ossification, and they also contribute to vascular development in multiple organs and fracture repair.

The Formation of the Epiphyseal Bone Plate Occurs via Combined Endochondral and Intramembranous-Like Ossification

“…In this way, although it is generally assumed that a long bone is formed by endochondral ossification, much of its postnatal ossification occurs subperiosteally and so is essentially intramembranous [ 8 ]. Additionally, a combination of both intramembranous and endochondral ossification has been reported to occur simultaneously during craniofacial bone development [ 9 ], clavicle formation [ 10 ], fracture healing of mandible [ 11 ], and bone lengthening through callus distraction [ 12 , 13 ].…”

Bone Development and Growth

“…Intramembranous and endochondral ossification are usually considered as separate modes of ossification; however, this is a simplification, since it has been reported that both occur simultaneously during the development of many bones [ 9 , 10 ]. Furthermore, although it is assumed that long bones are formed by endochondral ossification, much of their postnatal ossification occurs subperiosteally and so is essentially intramembranous.…”