Osteoporosis and ageing affects the migration of stem cells and this is ameliorated by transfection with CXCR4

Sanghani-Kerai, Anita; Coathup, Melanie; Samazideh, S.; Kalia, Priya; Silvio, L. Di; Idowu, Bernadine; Blunn, Gordon

doi:10.1302/2046-3758.66.bjr-2016-0259.r1

Cited by 40 publications

(30 citation statements)

References 31 publications

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“…Interestingly, Zhu et al (33) reported that conditioned media from PTH-treated osteoblasts and osteocytes contain soluble chemotactic factors for bone marrow mesenchymal progenitors. Many candidates could stimulate migration of progenitor cells from the vessel wall to the bone surface, including amphiregulin (33) SDF-1, (34) or MCP-1, all potent chemotactic factors for mesenchymal precursors, whose osteoblastic expression is strongly stimulated by iPTH. (35) Interestingly, we observed at day 28 an increase in MCP-1 expression in iPTH-treated bones only (Fig.…”

Section: Effects Of Ipth On the Vascular Transitional Networkmentioning

confidence: 99%

Parathyroid Hormone Remodels Bone Transitional Vessels and the Leptin Receptor-Positive Pericyte Network in Mice

Caire

Roche

Picot

et al. 2019

Journal of Bone and Mineral Research

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Intermittent parathyroid hormone (iPTH) is anti‐osteoporotic and affects bone vessels. Transitional capillaries close to the bone surface, which express both endomucin (Edm) and CD31, bear leptin receptor‐expressing (LepR) perivascular cells that may differentiate into osteoblasts. Increased numbers of type H endothelial cells (THEC; ie, Edmhi/CD31hi cells assessed by flow cytometry, FACS) are associated with higher bone formation in young mice. We hypothesized that iPTH administration impacts transitional vessels by expanding THECs. Four‐month‐old C57/Bl6J female mice were injected with PTH 1–84 (100 μg/kg/d) or saline (CT) for 7 or 14 days. We quantified LepR+, CD31+, Edm+ cells and THECs by FACS in hindlimb bone marrow, and Edm/LepR double immunolabelings on tibia cryosections. Additionally, we analyzed bone mRNA expression of 87 angiogenesis‐related genes in mice treated with either intermittent or continuous PTH (iPTH/cPTH) or saline (CT) for 7, 14, and 28 days. iPTH dramatically decreased the percentage of THECs by 78% and 90% at days 7 and 14, respectively, and of LepR+ cells at day 14 (–46%) versus CT. Immunolabeling quantification showed that the intracortical Edm+‐vessel density increased at day 14 under iPTH. In the bone marrow, perivascular LepR+ cells, connected to each other via a dendrite network, were sparser under iPTH at day 14 (–58%) versus CT. iPTH decreased LepR+ cell coverage of transitional vessels only (–51%), whereas the number of LepR+ cells not attached to vessels increased in the endocortical area only (+ 49%). Transcriptomic analyses showed that iPTH consistently upregulated PEDF, Collagen‐18α1, and TIMP‐1 mRNA expression compared with CT and cPTH. Finally, iPTH increased immunolabeling of endostatin, a Collagen‐18 domain that can be cleaved and become antiangiogenic, in both endocortical (79%) and peritrabecular transitional microvessels at day 14. Our results show that iPTH specifically remodels transitional vessels and suggest that it promotes LepR+ cell mobilization from these vessels close to the bone surface. © 2019 American Society for Bone and Mineral Research.

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Section: Effects Of Ipth On the Vascular Transitional Networkmentioning

confidence: 99%

Parathyroid Hormone Remodels Bone Transitional Vessels and the Leptin Receptor-Positive Pericyte Network in Mice

Caire

Roche

Picot

et al. 2019

Journal of Bone and Mineral Research

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“…Older rats have fewer CFUs, fewer MSCs in the bone marrow, possibly explaining the reduced yields in non‐mobilized controls and mobilized groups compared with Pitchford et al, who used young mice. Humans also show reduced CFUs with ageing and a recent study also showed an age relationship with CXCR4 dependent migration and hence the effect of antagonism of the CXCR4‐SDF1 axis may also reduce with age. Most of the studies looking at peripheral blood circulating stem cells and mobilization in animal models have used young immature animals, and therefore there may be merit in evaluating the role of age in mobilization potential.…”

Section: Discussionmentioning

confidence: 98%

VEGF with AMD3100 endogenously mobilizes mesenchymal stem cells and improves fracture healing

Meeson

Sanghani-Keri

Coathup

et al. 2018

Journal Orthopaedic Research

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A significant number of fractures develop non‐union. Mesenchymal stem cell (MSC) therapy may be beneficial, however, this requires cell acquisition, culture and delivery. Endogenous mobilization of stem cells offers a non‐invasive alternative. The hypothesis was administration of VEGF and the CXCR4 antagonist AMD3100 would increase the circulating pool of available MSCs and improve fracture healing. Ex‐breeder female wistar rats received VEGF followed by AMD3100, or sham PBS. Blood prepared for culture and colonies were counted. P3 cells were analyzed by flow cytometry, bi‐differentiation. The effect of mobilization on fracture healing was evaluated with 1.5 mm femoral osteotomy stabilized with an external fixator in 12–14 week old female Wistars. The mobilized group had significantly greater number of cfus/ml compared to controls, p = 0.029. The isolated cells expressed 1.8% CD34, 35% CD45, 61% CD29, 78% CD90, and differentiated into osteoblasts but not into adipocytes. The fracture gap in animals treated with VEGF and AMD3100 showed increased bone volume; 5.22 ± 1.7 µm 3 and trabecular thickness 0.05 ± 0.01 µm compared with control animals (4.3 ± 3.1 µm 3 , 0.04 ± 0.01 µm, respectively). Radiographic scores quantifying fracture healing (RUST) showed that the animals in the mobilization group had a higher healing score compared to controls (9.6 vs. 7.7). Histologically, mobilization resulted in significantly lower group variability in bone formation ( p = 0.032) and greater amounts of bone and less fibrous tissue than the control group. Clinical significance: This pre‐clinical study demonstrates a beneficial effect of endogenous MSC mobilization on fracture healing, which may have translation potential to prevent or treat clinical fractures at risk of delayed or non‐union fractures. © 2018 The Authors. Journal of Orthopaedic Research ® Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 37:1294–1302, 2019.

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“…Mesenchymal stem cells (MSC) are known to migrate to sites of injury in a response to chemical signals . Impaired recruitment of MSC to locations of bone remodeling is a proposed explanation for compromised bone formation . Unfortunately, studies involving systemic infusion of MSC have not shown that the cells are able to migrate to and engraft at fracture sites, although some have reported enhanced tissue repair despite the lack of engraftment .…”

Section: Featured Articlesmentioning

confidence: 99%

“…In these cases, they don't necessarily differentiate and replace the damaged tissue, but influence therapeutic change by migrating to the damaged tissue and mediating recovery through the action of other cell types . This mechanism of action depends on the ability of the cells to migrate to a disease site, which can be impaired in patients with severe disease . Determining ways in which we can recover or enhance the pathways that allow cells to respond to and migrate toward sites of damage could mitigate that issue.…”

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Stem Cells

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Osteoporosis and ageing affects the migration of stem cells and this is ameliorated by transfection with CXCR4

Cited by 40 publications

References 31 publications

Parathyroid Hormone Remodels Bone Transitional Vessels and the Leptin Receptor-Positive Pericyte Network in Mice

Parathyroid Hormone Remodels Bone Transitional Vessels and the Leptin Receptor-Positive Pericyte Network in Mice

VEGF with AMD3100 endogenously mobilizes mesenchymal stem cells and improves fracture healing

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