Subtypes of endothelial progenitor cells affect healing of segmental bone defects differently

Giles, Erica; Godbout, Charles; Chi, Wendy; Glick, Michael A.; Lin, Tony W.; Li, Ru; Schemitsch, Emil H.; Nauth, Aaron

doi:10.1007/s00264-017-3613-0

Cited by 12 publications

(21 citation statements)

References 28 publications

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“…The sum effect of osteogenic BMPs seems to be a net bone loss, resulting from their stronger effect on osteoclasts compared to osteoblasts. This was supported by the rat study showing superiority in treating fracture non-union with early endothelial progenitor cells, when compared to late endothelial progenitor cells which release more BMP2 [23]. These unexpected results are inconsistent with the in vitro evidence showing that BMP2 and 7 promote differentiation of various osteoblast-like cells and in vivo induce new bone formation at ectopic sites in experimental animals ( Fig.…”

Section: Molecular Interventions Into Bmp Bone Development and Growthmentioning

confidence: 93%

Bone morphogenetic proteins in fracture repair

Dumić-Čule

Perić

Kucko

et al. 2018

International Orthopaedics (SICOT)

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Bone fractures represent a significant medical morbidity among aged population with osteoporosis. Bone morphogenetic proteins (BMPs) are suggested to have therapeutic potential to enhance fracture healing in such patients. Though BMP-mediated fracture healing has been well-documented in preclinical models, there has been no clinical study that demonstrated unequivocally that indeed a BMP when presented with an appropriate scaffold could provide basis for robust outcome for delayed or non-union diaphyseal bone fractures. This review presents a comprehensive insight towards the existing knowledge on the role of BMP signaling in bone formation and maintenance. Also therapeutic options based on BMP biology are discussed.A novel osteoinductive autologous bone graft substitute (ABGS) aimed to accelerate bone regeneration was developed and is currently being tested in the clinical setting. It comprises of a biologically compatible autologous carrier made from the patient's peripheral blood (autologous blood coagulum, ABC) and of rhBMP6 as an active ingredient. Such formulation circumvents the use of animal-derived materials, significantly limits inflammatory processes common in commercial bone devices and renders the carrier flexible, malleable, and injectable ensuring the ease of use. The ongoing clinical trials result will provide more detailed insights into the safety, tolerability, pharmacokinetics, and bone healing effects in humans and potentially provide novel and safe therapeutic options for bone repair.

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Section: Molecular Interventions Into Bmp Bone Development and Growthmentioning

confidence: 93%

Bone morphogenetic proteins in fracture repair

Dumić-Čule

Perić

Kucko

et al. 2018

International Orthopaedics (SICOT)

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“…Although this review will focus on MSCS, all tissues require a robust vascular supply to maintain sufficient amounts of oxygen and nutrients, and rid the tissues of toxic waste. These concepts are also relevant to fracture healing and bone regeneration (Lee et al, 2008 ; Giles et al, 2017 ; Bahney et al, 2019 ). Endothelial progenitor cells are found in aspirates of the iliac crest, and in other sources commonly harvested for bone graft, however the numbers of endothelial colony-forming units (ECFCs) from these sources is very low (Pittenger et al, 1999 ).…”

Section: Introductionmentioning

confidence: 99%

Modifying MSC Phenotype to Facilitate Bone Healing: Biological Approaches

Goodman

Lin

2020

Front. Bioeng. Biotechnol.

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Healing of fractures and bone defects normally follows an orderly series of events including formation of a hematoma and an initial stage of inflammation, development of soft callus, formation of hard callus, and finally the stage of bone remodeling. In cases of severe musculoskeletal injury due to trauma, infection, irradiation and other adverse stimuli, deficient healing may lead to delayed or non-union; this results in a residual bone defect with instability, pain and loss of function. Modern methods of mechanical stabilization and autologous bone grafting are often successful in achieving fracture union and healing of bone defects; however, in some cases, this treatment is unsuccessful because of inadequate biological factors. Specifically, the systemic and local microenvironment may not be conducive to bone healing because of a loss of the progenitor cell population for bone and vascular lineage cells. Autologous bone grafting can provide the necessary scaffold, progenitor and differentiated lineage cells, and biological cues for bone reconstruction, however, autologous bone graft may be limited in quantity or quality. These unfavorable circumstances are magnified in systemic conditions with chronic inflammation, including obesity, diabetes, chronic renal disease, aging and others. Recently, strategies have been devised to both mitigate the necessity for, and complications from, open procedures for harvesting of autologous bone by using minimally invasive aspiration techniques and concentration of iliac crest bone cells, followed by local injection into the defect site. More elaborate strategies (not yet approved by the U.S. Food and Drug Administration-FDA) include isolation and expansion of subpopulations of the harvested cells, preconditioning of these cells or inserting specific genes to modulate or facilitate bone healing. We review the literature pertinent to the subject of modifying autologous harvested cells including MSCs to facilitate bone healing. Although many of these techniques and technologies are still in the preclinical stage and not yet approved for use in humans by the FDA, novel approaches to accelerate bone healing by modifying cells has great potential to mitigate the physical, economic and social burden of non-healing fractures and bone defects.

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“…Some researchers tried to make prevascularized MSC sheets by seeding endothelial cells on them to enhance vascularization after implantation [ 20 ]. Endothelial progenitor cells (EPCs) are attractive candidates to address vascular issues [ 21 ] and have been found to participate in vessel regeneration after brain radiation in mice [ 22 ]. It is of interest to test whether EPCs could be used in combination with BMSC sheets to improve bone healing in irradiated bone.…”

Section: Introductionmentioning

confidence: 99%

Endothelial progenitor cells improve the therapeutic effect of mesenchymal stem cell sheets on irradiated bone defect repair in a rat model

Liu

Jiao²,

Zhou

et al. 2018

J Transl Med

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BackgroundThe reconstruction of bone defects is often impaired by radiotherapy since bone quality is compromised by radiation. This study aims to investigate the therapeutic efficacy of the composite cell sheets-bone marrow mesenchymal stem cell (BMSC) sheets cocultured with endothelial progenitor cells (EPCs)-in the healing of irradiated bone defects and the biological effects of EPCs on the osteogenic properties of BMSC sheets.MethodsBMSCs and EPCs were isolated from rat bone marrow. BMSCs were used to form cell sheets by the vitamin C inducing method. EPCs were seeded on BMSC sheets to make EPCs–BMSC sheets. Osteogenesis of EPCs–BMSC sheets and BMSC sheets were tested. In vitro osteogenesis tests included ALP, Alizarin Red S, Sirius Red staining, qRT-PCR and Western blot analysis after 3 and 7 days of osteogenic incubation. Subcutaneous osteogenesis was tested by H&E staining and immunohistochemical staining 8 weeks after transplantation. EPCs–BMSC sheets and BMSC sheets were used in the 3 mm defects of non-irradiated and irradiated rat tibias. Micro-CT and histological analysis were used to test the healing of bone defects 4 and 8 weeks after transplantation.ResultsEPCs–BMSC sheets showed enhanced osteogenic differentiation in vitro with increased expression of osteoblastic markers and osteogenesis related staining compared with BMSC sheets. In subcutaneous osteogenesis test, EPCs–BMSC sheets formed larger areas of new bone and blood vessels. The EPCs–BMSC group had the highest volume of newly formed bone in the defect area of irradiated tibias.ConclusionsEPCs improved the osteogenic differentiation of BMSC Sheets and enhanced the ectopic bone formation. EPCs–BMSC sheets promoted bone healing in irradiated rat tibias. EPCs–BMSC sheets are potentially useful in the reconstruction of bone defect after radiotherapy.Electronic supplementary materialThe online version of this article (10.1186/s12967-018-1517-4) contains supplementary material, which is available to authorized users.

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Subtypes of endothelial progenitor cells affect healing of segmental bone defects differently

Abstract: We demonstrated that bone marrow-derived E-EPCs are a better alternative than L-EPCs for treatment of nonunion. We hypothesize that the expression profile of E-EPCs and their adaptation to the local environment contribute to superior bone healing.

Cited by 12 publications

References 28 publications

Bone morphogenetic proteins in fracture repair

Bone morphogenetic proteins in fracture repair

Modifying MSC Phenotype to Facilitate Bone Healing: Biological Approaches

Endothelial progenitor cells improve the therapeutic effect of mesenchymal stem cell sheets on irradiated bone defect repair in a rat model

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