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Cell therapy: potential of mesenchymal stem cells, VEGF-A and BMP-9 to regenerate bone tissue

Grant number: 17/12622-7
Support type:Research Projects - Thematic Grants
Duration: August 01, 2018 - July 31, 2023
Field of knowledge:Health Sciences - Dentistry
Principal Investigator:Adalberto Luiz Rosa
Grantee:Adalberto Luiz Rosa
Home Institution: Faculdade de Odontologia de Ribeirão Preto (FORP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Co-Principal Investigators:Márcio Mateus Beloti
Assoc. researchers: Gary S. Stein ; Geraldo Aleixo da Silva Passos Júnior ; Jane Lian ; Janet L. Stein ; José César Rosa ; Karina Fittipaldi Bombonato Prado ; Marília Afonso Rabelo Buzalaf ; Paulo Tambasco de Oliveira
Associated grant(s):19/05289-5 - Multi-User Equipment approved in grant 2017/21622-7: aparelho QuantStudio 7 Flex Real-Time PCR System, AP.EMU
19/05291-0 - Multi-use equipment approved in grant 2017/12622-7:SkyScan 1276 high resolution desktop in-vivo microtomograph, AP.EMU
Associated scholarship(s):19/10076-0 - Effect of mesenchymal stem cells from periodontal ligament with high and low osteogenic potential on bone repair, BP.MS
19/01344-1 - Evaluation of the osteogenic and bone tissue regeneration potentials of BM-MSCs and AT-MSCs associated with VEGF-A and BMP-9, BP.PD
19/01346-4 - Evaluation of the angiogenic and bone regeneration potentials of BM-MSCs and AT-BMCs genetically edited by CRISP-Cas9 to overexpress VEGF-A and BMP-9, BP.PD
+ associated scholarships 18/13290-0 - Cell therapy: evaluation of the effect of mesenchymal stem cells to regenerate bone tissue of rats with Osteoporosis, Diabetes Mellitus or Arterial Hypertension, BP.DR
18/19559-1 - Evaluation of the angiogenic and bone healing potential of BM-MSCs and AT-MSCs combined with VEGF-A and BMP-9, BP.IC
18/16852-0 - Study of the angiogenic potential and of the capacity to regenerate bone tissue of BM-MSCs and AT-MSCs associated with VGFA-A and BMP-9, BP.IC - associated scholarships

Abstract

Bone tissue has high capacity of regeneration, but in several situations the extent of the injury overcomes its regenerative potential. In this scenario, therapies based on the use of mesenchymal stem cells (MSCs) have aroused the attention of many researchers for being a promising alternative compared with the available treatments. However, many molecular, cellular and tissue characteristics remain unmet in the literature to make cell therapy an effective treatment for bone repair both in healthy and systemic compromised patients by pathologies such as osteoporosis, diabetes and hypertension. In keeping with this, this research project consists of three subprojects that aim to: (1) evaluate the potential of MSCs harvested from either bone marrow (BM-MSCs) or adipose tissue (AT-MSCs) combined with vascular endothelial growth factor A (VEGF-A) and/or bone morphogenetic protein 9 (BMP-9) to repair bone defects; (2) evaluate the potential of these MSCs genetically edited to overexpress VEGF-A and/or BMP-9 to repair bone defects; and (3) evaluate the effect of BM-MSCs harvested from healthy rats on the osteoblastic differentiation of BM-MSCs harvested from osteoporotic, diabetic and hypertensive rats. To develop subprojects 1 and 2, BM-MSCs and AT-MSCs will be treated with VEGF-A and/or BMP-9 or genetically edited by clustered regularly interspaced short palindromic repeats (CRISPR-Cas9) to overexpress VEGF-A and/or BMP-9. Those cells will be evaluated in vitro to assess their angiogenic and osteogenic potentials as well as their large scale genomic and proteomic profile. For bone repair, BM-MSCs and AT-MSCs either combined with VEGF-A and/or BMP-9 or edited to overexpress these factors will be directly injected into rat bone calvarial defects. To evaluate the presence of cells in the defects, Luc-expressing cells will be tracked by bioluminescent imaging. Up to 4 weeks, vasculogenesis and bone formation will be evaluated by in vivo micro-CT. After 4 weeks, the animals will be euthanized and the harvested calvaria evaluated by histological analysis. In the subproject 3, the effect of BM-MSCs harvested from healthy rats on the osteoblastic differentiation of BM-MSCs from osteoporotic, diabetic and hypertensive rats will be evaluated using an indirect co-culture model. These studies are the first step aiming to apply these cell therapies to regenerate bone defects in the presence of such pathologies. (AU)