Activation of Skeletal Stem and Progenitor Cells for Bone Regeneration Is Driven by PDGFRβ Signaling

Böhm, Anna-Marei; Dirckx, Naomi; Tower, Robert J.; Peredo, Nicolas; Vanuytven, Sebastiaan; Theunis, Koen; Nefyodova, Elena; Cardoen, Ruben; Lindner, Volkhard; Voet, Thierry; Hul, Matthias Van; Maes, Christa

doi:10.1016/j.devcel.2019.08.013

Cited by 77 publications

(99 citation statements)

References 74 publications

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“…In Fig. S3, ONFHexos augmented the number of MSCs by increasing proliferation and decreasing apoptosis, which might be the compensation to the ischemic injury 40,41 . These data indicated that exosomes from the necrotic zone aggravated ONFH by influencing osteogenic differentiation and migration of MSCs.…”

Section: Discussionmentioning

confidence: 90%

CD41-deficient exosomes from non-traumatic femoral head necrosis tissues impair osteogenic differentiation and migration of mesenchymal stem cells

Zhu

Guo

et al. 2020

Cell Death Dis

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Non-traumatic osteonecrosis of the femoral head (ONFH) is clinically a devastating and progressive disease without an effective treatment. Mesenchymal stem cells (MSCs) transplantation has been used to treat ONFH in early stage, but the failure rate of this therapy is high due to the reduced osteogenic differentiation and migration of the transplanted MSCs related with pathological bone tissues. However, the mechanism responsible for this decrease is still unclear. Therefore, we assume that the implanted MSCs might be influenced by signals delivered from pathological bone tissue, where the exosomes might play a critical role in this delivery. This study showed that exosomes from ONFH bone tissues (ONFH-exos) were able to induce GC-induced ONFH-like damage, in vivo and impair osteogenic differentiation and migration of MSCs, in vitro. Then, we analyzed the differentially expressed proteins (DEPs) in ONFHexos using proteomic technology and identified 842 differentially expressed proteins (DEPs). On the basis of gene ontology (GO) enrichment analysis of DEPs, fold-changes and previous report, cell adhesion-related CD41 (integrin α2b) was selected for further investigation. Our study showed that the CD41 (integrin α2b) was distinctly decreased in ONFH-exos, compared to NOR-exos, and downregulation of CD41 could impair osteogenic differentiation and migration of the MSCs, where CD41-integrin β3-FAK-Akt-Runx2 pathway was involved. Finally, our study further suggested that CD41-affluent NOR-exos could restore the glucocorticoid-induced decline of osteogenic differentiation and migration in MSCs, and prevent GC-induced ONFH-like damage in rat models. Taken together, our study results revealed that in the progress of ONFH, exosomes from the pathological bone brought about the failure of MSCs repairing the necrotic bone for lack of some critical proteins, like integrin CD41, and prompted the progression of experimentally induced ONFH-like status in the rat. CD41 could be considered as the target of early diagnosis and therapy in ONFH.

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Section: Discussionmentioning

confidence: 90%

CD41-deficient exosomes from non-traumatic femoral head necrosis tissues impair osteogenic differentiation and migration of mesenchymal stem cells

Zhu

Guo

et al. 2020

Cell Death Dis

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“…(87) Further, PDGFRβ + skeletal stem and progenitor cells (SSPCs) mainly reside in perivascular niches, and PDGF-PDGFRβ signaling induces SSPC proliferation, trafficking, and angiotropism during bone injury. (88) (106) ; Basic-Jukic and colleagues (147) BMP-4 ; Klimiuk and colleagues (142) ; Zimmermann-Geller and colleagues (143) FGF1 (60) ; Dias and colleagues (61) IL-33 Romeo and colleagues (39) Nidogen-1 ; Song and colleagues (38) Tenascin-C Romeo and colleagues (39) TNF-α Carlson and colleagues (182) Vascular roles of fibroblast growth factor Fibroblast growth factors (FGFs) are mainly secreted by bone lineage cells, including chondrocytes and osteoblasts, (89,90) and the receptors FGFR1 and FGFR2 expressed in vascular cells. (91) FGFs induces the expression of multiple angiogenic molecules, including VEGFA and VEGFR2, stimulating the growth of blood vessels and contributing to chondrocyte proliferation and the initiation of chondrocyte hypertrophy.…”

Section: Role Of Vegfa During Bone Developmentmentioning

confidence: 99%

Bone Vasculature and Bone Marrow Vascular Niches in Health and Disease

Chen

Hendriks

Chatzis

et al. 2020

Journal of Bone and Mineral Research

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Bone vasculature and bone marrow vascular niches supply oxygen, nutrients, and secrete angiocrine factors required for the survival, maintenance, and self-renewal of stem and progenitor cells. In the skeletal system, vasculature creates nurturing niches for bone and blood-forming stem cells. Blood vessels regulate hematopoiesis and drive bone formation during development, repair, and regeneration. Dysfunctional vascular niches induce skeletal aging, bone diseases, and hematological disorders. Recent cellular and molecular characterization of the bone marrow microenvironment has provided unprecedented insights into the complexity, heterogeneity, and functions of the bone vasculature and vascular niches. The bone vasculature is composed of distinct vessel subtypes that differentially regulate osteogenesis, hematopoiesis, and disease conditions in bones. Further, bone marrow vascular niches supporting stem cells are often complex microenvironments involving multiple different cell populations and vessel subtypes. This review provides an overview of the emerging vascular cell heterogeneity in bone and the new roles of the bone vasculature and associated vascular niches in health and disease.

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“…Indeed, LepR+ cells express both PDGFRα ( Pdgfra ) and PDGFRβ ( Pdgfrb ) ( Sugiyama et al, 2006 ; Zhou B.O. et al, 2014 ), whose ligands PDGF-B and PDGF-D are produced by endothelial cells (and pre-osteoclasts) ( Xie et al, 2014 ; Böhm et al, 2019 ). The existence of such crosstalk is supported by the recent finding that ablation of PDGFRβ from Osx-Cre-positive cells has no effect on bone formation, but lowers the contribution of Osx-traced cells to fracture healing and impaired vascularization of the callus ( Böhm et al, 2019 ).…”

Section: The Perivascular Niche In Adult Bonementioning

confidence: 99%

“…This aligns well with the previous observation that Osx-Cre mediated ablation of β-catenin causes a shift of the fate of targeted cells to the adipogenic line ( Song et al, 2012 ). However, in this context it should not be forgotten that Osx-Cre targets a number of different types of cells, including osteoprogenitors, pericytes and bm-SSPCs ( Mizoguchi et al, 2014 ; Böhm et al, 2019 ).…”

Section: The Perivascular Niche In Adult Bonementioning

confidence: 99%

“…Several markers – including Grem1 ( Worthley et al, 2015 ), Gli1 ( Shi et al, 2017 ), LepR ( Zhou B.O. et al, 2014 ), Osx (at its multipotency stage, Mizoguchi et al, 2014 ), PDGFRβ ( Böhm et al, 2019 ), Prx1 ( Greenbaum et al, 2013 ), Nestin-GFP ( Ono et al, 2014a ), and Col2 ( Ono et al, 2014b ) – reveal the presence of putative stem cells in the region of the primary spongiosa, immediately below the growth plate. The primary spongiosa is a unique area characterized by intensive bone formation and tissue remodeling.…”

Section: Skeletal Stem and Progenitor Cells In Developing Bonementioning

confidence: 99%

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Niches for Skeletal Stem Cells of Mesenchymal Origin

Kurenkova

Medvedeva

Newton

et al. 2020

Front. Cell Dev. Biol.

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With very few exceptions, all adult tissues in mammals are maintained and can be renewed by stem cells that self-renew and generate the committed progeny required. These functions are regulated by a specific and in many ways unique microenvironment in stem cell niches. In most cases disruption of an adult stem cell niche leads to depletion of stem cells, followed by impairment of the ability of the tissue in question to maintain its functions. The presence of stem cells, often referred to as mesenchymal stem cells (MSCs) or multipotent bone marrow stromal cells (BMSCs), in the adult skeleton has long been realized. In recent years there has been exceptional progress in identifying and characterizing BMSCs in terms of their capacity to generate specific types of skeletal cells in vivo . Such BMSCs are often referred to as skeletal stem cells (SSCs) or skeletal stem and progenitor cells (SSPCs), with the latter term being used throughout this review. SSPCs have been detected in the bone marrow, periosteum, and growth plate and characterized in vivo on the basis of various genetic markers (i.e., Nestin, Leptin receptor, Gremlin1, Cathepsin-K, etc.). However, the niches in which these cells reside have received less attention. Here, we summarize the current scientific literature on stem cell niches for the SSPCs identified so far and discuss potential factors and environmental cues of importance in these niches in vivo . In this context we focus on (i) articular cartilage, (ii) growth plate cartilage, (iii) periosteum, (iv) the adult endosteal compartment, and (v) the developing endosteal compartment, in that order.

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Activation of Skeletal Stem and Progenitor Cells for Bone Regeneration Is Driven by PDGFRβ Signaling

Cited by 77 publications

References 74 publications

CD41-deficient exosomes from non-traumatic femoral head necrosis tissues impair osteogenic differentiation and migration of mesenchymal stem cells

CD41-deficient exosomes from non-traumatic femoral head necrosis tissues impair osteogenic differentiation and migration of mesenchymal stem cells

Bone Vasculature and Bone Marrow Vascular Niches in Health and Disease

Niches for Skeletal Stem Cells of Mesenchymal Origin

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