Skeletal stem cells: insights into maintaining and regenerating the skeleton

Serowoky, Maxwell A; Arata, Claire; Crump, J. Gage; Mariani, Francesca V.

doi:10.1242/dev.179325

Cited by 48 publications

(49 citation statements)

References 94 publications

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“…Here, we reported, for the first time, that AC also houses a class of Col2+ progenitors. Interestingly, we found that Col2+ cells in AC are similar to Pthrp+ cells 30 and Col2+ cells 3,31 in GP, and few can differentiate into adipocytes in vitro . Most interestingly, Col2+ in GP has a stronger osteogenic and chondrogenic differentiation ability than that in articular chondrocytes and BMSCs.…”

Section: Discussionmentioning

confidence: 76%

“…They are generally defined as self-renewing cells with the “trilineage” potential to differentiate into chondrocytes, osteoblasts and adipocytes. To date, there are three types of SSCs depending on their location: bone marrow-derived SSCs, GP SSCs (a cartilaginous structure separating the primary and secondary ossification centers in growing bones) and perichondrial/periosteal SSCs (the connective tissue surrounding bone) 3,18 . Previous studies have revealed that Col2+ cells in bone marrow, GP and perichondrial/periosteal behave as SSCs 3,29 .…”

Section: Discussionmentioning

confidence: 99%

“…Multipotent mesenchymal stromal cells (MSCs) have been defined in culture as nonhematopoietic, plastic-adherent and colony-forming cells, which can differentiate into osteogenic, chondrogenic, and adipogenic progeny 1,2 . Recent studies have provided important insights into skeletal progenitor cells in vivo by using lineage tracing techniques 3 . Leptin receptor positive (Lepr+) 4,5 , chemokine (C-X-C motif) ligand 12 positive (Cxcl12+) 6 , Gli1+ 7 , Prx+ 8 , Nestin+ 9 , type II collagen-positive (Col2+) 10,11 , Sox9+ 11 , Aggrecan positive (Acan+) 11 and Ctsk+ 12 cells have been reported to label MSCs and play important roles during bone development and homeostasis.…”

Section: Introductionmentioning

confidence: 99%

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

Yang

Jing

et al. 2020

Preprint

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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.

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Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Yang

Jing

et al. 2020

Preprint

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“…This could explain the findings in our study that osteoblasts may use different types of scaffolds for bone deposition during the formation of the epiphyseal bone plate. In this way, it is well known that osteoblasts can respond differently to stimuli depending on the bone compartment where they are located [ 33 ]. It has been reported that osteoblasts at the metaphyseal side of the growth plate radically change the mode of bone deposition to form a proper horizontal bone plate after surgical excision of the growth plate and subsequent reimplantation in the inverted orientation [ 34 , 35 ].…”

Section: Discussionmentioning

confidence: 99%

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

Fernández-Iglesias

Fuente

Gil‐Peña

et al. 2021

IJMS

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The formation of the epiphyseal bone plate, the flat bony structure that provides strength and firmness to the growth plate cartilage, was studied in the present study by using light, confocal, and scanning electron microscopy. Results obtained evidenced that this bone tissue is generated by the replacement of the lower portion of the epiphyseal cartilage. However, this process differs considerably from the usual bone tissue formation through endochondral ossification. Osteoblasts deposit bone matrix on remnants of mineralized cartilage matrix that serve as a scaffold, but also on non-mineralized cartilage surfaces and as well as within the perivascular space. These processes occur simultaneously at sites located close to each other, so that, a core of the sheet of bone is established very quickly. Subsequently, thickening and reshaping occurs by appositional growth to generate a dense parallel-fibered bone structurally intermediate between woven and lamellar bone. All these processes occur in close relationship with a cartilage but most of the bone tissue is generated in a manner that may be considered as intramembranous-like. Overall, the findings here reported provide for the first time an accurate description of the tissues and events involved in the formation of the epiphyseal bone plate and gives insight into the complex cellular events underlying bone formation at different sites on the skeleton.

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“…Recent reports on the molecular identity of periosteal progenitors that contribute to fracture callus have used lineage tracing to identify a number of non-unique genes that mark this population [20]. Earlier work demonstrated high GFP reporter expression in periosteal cells of 3.6Col1a1-GFP mice and showed that 3.6Col1a1 marks cells of the osteoblast lineage [21].…”

Section: Introductionmentioning

confidence: 99%

Ablation of Proliferating Osteoblast Lineage Cells After Fracture Leads to Atrophic Nonunion in a Mouse Model

Hixon

Sykes

Yoneda

et al. 2020

Preprint

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Nonunion is defined as the permanent failure of a fractured bone to heal, often necessitating surgical intervention. Atrophic nonunions are a subtype that are particularly difficult to treat. Animal models of atrophic nonunion are available; however, these require surgical or radiation induced trauma to disrupt periosteal healing. While these approaches can result in nonunion, such invasive methods are not representative of many clinical nonunions where osseous regeneration has been arrested by a “failure of biology”. We hypothesized that arresting osteoblast cell proliferation after fracture would lead to atrophic nonunion in mice. Using mice that express a thymidine kinase (tk) ‘suicide gene’ driven by the 3.6Col1a1 promoter (Col1-tk), proliferating osteoblast lineage cells can be ablated upon exposure to the nucleoside analog ganciclovir (GCV). Wild-type (WT; control) and Col1-tk littermates were subjected to a full femur fracture and intramedullary fixation at 12 weeks old. Post injury, mice were dosed with GCV twice daily for 2 or 4 weeks. Histologically, we confirmed abundant tk+ expression in fracture callus, and diminished periosteal cell proliferation in Col1-tk mice at 3 weeks post fracture. Moreover, Col1-tk mice had less osteoclast activity, mineralized callus, and vasculature at the fracture site compared to WT mice. Additional mice were monitored for 12 weeks with in vivo radiographs and microCT scans, which revealed delayed bone bridging and reduced callus size in Col1-tk mice. Following sacrifice, ex vivo microCT and histology demonstrated failed union with residual bone fragments and fibrous tissue in Col1-tk mice. Biomechanical testing demonstrated an inability to recover torsional strength in Col1-tk mice compared to WT. Our data indicates that suppression of proliferating osteoblast-lineage cells for either 2 or 4 weeks after fracture blunts the formation and remodeling of a mineralized callus leading to a functional nonunion. We propose this as a new murine model of atrophic nonunion.

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Skeletal stem cells: insights into maintaining and regenerating the skeleton

Cited by 48 publications

References 94 publications

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

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

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

Ablation of Proliferating Osteoblast Lineage Cells After Fracture Leads to Atrophic Nonunion in a Mouse Model

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