Osteoclasts promote the formation of hematopoietic stem cell niches in the bone marrow

Mansour, Anna; Abou-Ezzi, Grazia; Sitnicka, Ewa; Jacobsen, Sten Eirik W.; Wakkach, Abdelilah; Blin-Wakkach, Claudine

doi:10.1083/jcb1965oia6

Cited by 52 publications

(75 citation statements)

References 45 publications

(91 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These unprecedented findings validate the physiological nature of the in vivo-established ossicle and reinforce the evidence of self-organization ability of hMSC-based hypertrophic cartilage templates into functional hematopoietic niches. Interestingly, the increased amount of hostderived BM in response to IL-1β seemed to mirror the enhanced osteoclast recruitment, as recently outlined in the context of HSC niches in a murine model (25). The developed system, although requiring further investigations to specify the mode of establishment (e.g., a direct vs. indirect niche effect of the human cells in triggering homing of the mouse HSC), offers the opportunity to address a variety of critical questions at the interface between HSC biology and regenerative medicine.…”

Section: Discussionmentioning

confidence: 89%

Engineering of a functional bone organ through endochondral ossification

Scotti

Piccinini

Takizawa

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

279

295

View full text Add to dashboard Cite

Embryonic development, lengthening, and repair of most bones proceed by endochondral ossification, namely through formation of a cartilage intermediate. It was previously demonstrated that adult human bone marrow-derived mesenchymal stem/stromal cells (hMSCs) can execute an endochondral program and ectopically generate mature bone. Here we hypothesized that hMSCs pushed through endochondral ossification can engineer a scaled-up ossicle with features of a "bone organ," including physiologically remodeled bone, mature vasculature, and a fully functional hematopoietic compartment. Engineered hypertrophic cartilage required IL-1β to be efficiently remodeled into bone and bone marrow upon subcutaneous implantation. This model allowed distinguishing, by analogy with bone development and repair, an outer, cortical-like perichondral bone, generated mainly by host cells and laid over a premineralized area, and an inner, trabecular-like, endochondral bone, generated mainly by the human cells and formed over the cartilaginous template. Hypertrophic cartilage remodeling was paralleled by ingrowth of blood vessels, displaying sinusoid-like structures and stabilized by pericytic cells. Marrow cavities of the ossicles contained phenotypically defined hematopoietic stem cells and progenitor cells at similar frequencies as native bones, and marrow from ossicles reconstituted multilineage long-term hematopoiesis in lethally irradiated mice. This study, by invoking a "developmental engineering" paradigm, reports the generation by appropriately instructed hMSC of an ectopic "bone organ" with a size, structure, and functionality comparable to native bones. The work thus provides a model useful for fundamental and translational studies of bone morphogenesis and regeneration, as well as for the controlled manipulation of hematopoietic stem cell niches in physiology and pathology.

show abstract

Section: Discussionmentioning

confidence: 89%

Engineering of a functional bone organ through endochondral ossification

Scotti

Piccinini

Takizawa

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

279

295

View full text Add to dashboard Cite

show abstract

“…Recent studies have emerged describing reduced numbers of HSCs in a variety of genetically engineered mice with significantly increased bone density phenotypes, including osteopetrosis and osteosclerosis. (28)(29)(30) In contrast, our mice had normal bone mass, as ZA was used only to prevent therapyinduced bone loss. Our data suggest that inhibiting osteoclasts before cancer therapy to prevent bone loss may be beneficial to the outcome of patients without having further detrimental effects on HSCs.…”

Section: Discussionmentioning

confidence: 91%

Myelosuppressive Therapies Significantly Increase Pro-Inflammatory Cytokines and Directly Cause Bone Loss

Quach

Askmyr

Jovic

et al. 2014

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

Skeletal-related events resulting from accelerated bone loss are common complications in patients treated for a range of cancers. However, the mechanisms and rate of bone loss after myelosuppression are unclear. We, therefore, investigated this in mice and humans. We treated mice with different myelosuppressive therapies (chemotherapy or irradiation with or without transplantation) and studied their effects on bone structure. Myelosuppression of mice rapidly caused an increase in bone resorption that was not matched by bone formation. The resultant significant and persistent bone loss early after therapy was associated with increased inflammatory cytokines, in particular, monocyte chemoattractant protein 1 (MCP1). Therapy-induced bone loss was prevented with a single dose of the bisphosphonate zoledronic acid (ZA), administered before myelosuppression. Importantly, ZA treatment of mice did not impair hematopoiesis, including hematopoietic stem cell function. Furthermore, examination of serum from patients before and after autologous or allogeneic stem cell transplantion (SCT) revealed altered levels of bone turnover markers and elevated inflammatory cytokines. MCP1 levels in serum obtained between days 7 and 14 post-SCT positively correlated with bone loss observed at 100 days after allogeneic SCT. Similar to that observed in our studies in mice, the bone loss was long term, persisting at 12 months post-SCT. Furthermore, patients who received chemotherapy less than 100 days before SCT had significantly more bone loss at the hip. In these patients, serum levels of MCP1, but not routine biomarkers of bone turnover, including C-terminal crosslinking telopeptide of type-1 collagen (b-CTx), positively correlated with their bone loss. Hence, myelosuppressive therapies increase inflammation and directly contribute to bone loss. Administration of an osteoclast inhibitor before the initiation of cancer therapy is likely to have the best outcome in preventing bone loss in patients with cancer.

show abstract

“…It has also been reported that osteoclasts play a major role in HSC niche formation. Oc/oc mice, in which osteoclasts are inactive due to the loss of normal proton production, leading to severe osteopetrosis, show a dramatic reduction in HSCs and impaired osteoblastic commitment, without deficits in perivascular mesenchymal cells [26]. This result indicates that active osteoclasts are indispensable for endosteal HSC/ HPC niche formation.…”

Section: Osteoblast Progenitor (Pre-osteoblast) and Osteoblastmentioning

confidence: 96%

Regulation of hematopoiesis in endosteal microenvironments

Asada

Katayama

2014

Int J Hematol

View full text Add to dashboard Cite

After birth, the hematopoietic system develops along with bone formation in mammals. Osteolineage cells are derived from mesenchymal progenitor cells, and differentiate into several types of bone-forming cells. Of the various types of cell constituents in bone marrow, osteolineage cells have been shown to play important roles in hematopoiesis. Early studies have identified osteoblasts as a hematopoietic stem cell niche component. Since that time, the role of endosteal microenvironment as a critical regulator of hematopoietic stem/progenitor cell (HSC/ HPC) behavior has been appreciated particularly under stress conditions, such as cytokine-induced HSC/HPC mobilization, homing/engraftment after bone marrow transplantation, and disease models of leukemia/myelodysplasia. Recent studies revealed that the most differentiated osteolineage cells, i.e., osteocytes, play important roles in the regulation of hematopoiesis. In this review, we provide an overview of recent advances in knowledge of regulatory hematopoietic mechanisms in the endosteal area.

show abstract

Osteoclasts promote the formation of hematopoietic stem cell niches in the bone marrow

Cited by 52 publications

References 45 publications

Engineering of a functional bone organ through endochondral ossification

Engineering of a functional bone organ through endochondral ossification

Myelosuppressive Therapies Significantly Increase Pro-Inflammatory Cytokines and Directly Cause Bone Loss

Regulation of hematopoiesis in endosteal microenvironments

Contact Info

Product

Resources

About