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osteoporosis
- 1. Direct conversion of fibroblast to osteoblast as a novel strategy for bone regeneration in elderly individuals Presented by: Sahibzada M. Adn FA18-R02-016
- 2. Osteoporosis ο Bone weakening ο Develop in elderly people
- 3. Osteoblast ο Cell with single nucleus ο Generate factors such as osteopontin and osteocalcin ο They synthesize dense cross linked collagen and specialized proteins ο Compose the organic matrix of bones
- 4. Osteoclast ο Responsible for bone resorption results in break down of bone tissue ο Deposition of bones trigger by enzyme secreted by osteoclast
- 5. Importance of bone homeostasis Bone homeostasis consist of two process
- 7. Association of osteoporosis and bone fracture with aging A) Change in sex hormones B) Inflammation C) Metabolic complications
- 8. Problems with aging ο Aging result in senescene related events that trigger oxidative stress ο Affect the generation and apoptosis of osteoblast ο Impaired osteoblastogenesis ο Elasticity of the bone matrix change the bone mass decreases ο Bone homeostasis disturb with increase resorption and decrease formation
- 9. Strategies Bone tissue engineering 1) Implantation of autogenous bone Bone transfer from one site to another in the same patient Limitation ο Graft resorption ο Donor site morbidity ο Limited availability ο Operative time for harvesting graft
- 10. 2) Allograft Transplantion of cells, tissues, or organs to a recipient from a genetically non- identical donor of the same species. Limitation ο High cost ο Possibility of disease transmission ο Lack of osteoinduction
- 11. 3) Immune engineering ο Alteration of immune system to boost bone repair and regeneration ο Bone fractures attracts inflammatory cytokines and growth factors Limitation ο Abberant inflammation ο Autoimmune disorder ο Suppress osteogenesis
- 12. 4) Hydrogels ο Comprise a group of polymeric material ο Mimic the extracellular matrix topography and deliver bioactive agents Limitations ο Difficulty in controlling the release of encapsulated bioactive molecules ο Toxic reactions due to use of
- 13. 6 induced pluricpotent stem cells (IPSCs) ο Differentiate into range of different cell types ο In vivo transplantation IPSCs derived osteoblast report to lead mineralization and formation of bone matrix Limitation ο Time consuming procedure ο Ethical and safety concerns in transplantation in human ο Immunological rejection response ο Possibility of teratoma formation
- 14. For cartilage- and bone tissue engineering applications
- 15. 5) BM-MSCs ο Owing to their osteogenic potential can be transplanted to repair bone defect Limitation ο Restricted in elderly people due to limited yeild ο Expandibility of BM-MSCs ο Ability of these cells to differentiate into osteoblasts
- 16. Direct reprogramming ο Conversion of somatic cells into specific cell types ο Without passing through an intermediate stage ο Introduction of lineage specific factor
- 17. History ο First introduce by Davis ο Demonstrated that fibroblast can be converted into myoblast by ecotopic expression of the muscle specific factors ο have reported that specific transcription factors can induce somatic cell to form various cell types including ο Cardiomycetes ο Neuron ο Hemotopoitic progenitor cell ο Pancreatic beta cell
- 18. Direct reprogramming ο Without a transient pluripotent stage ο 3 factors ASCL1, brn2, Mtyll require for conversion of fibroblast into neuron ο 3 factors Gata4, Hnf1a, and Foxa3 conversion of fibroblast into hepatocyte like cell ο 3 factors Ngn3, Pdx1, Mafa conversion of panereatic exocrine cell into B cell
- 19. Direct reprograming into osteoblasts ο In 2015 yamonoto first reported that human fibroblst can be converted into osteoblast using transcription factors ο Osterix ο Runt related transcription factor 2 (Runx2) ο Octamer binding transcription factor 4 (Oct4) ο L-myc
- 20. Contβ¦ ο Factors are regulators of osteoblast development ο Over all gene expression profile of induced osteoblast was similar to that of osteoblast ο IOBs have an osteogenic morphology ο Production of bone matrix ο Expression of osteoblast related genes
- 21. IOBs ο IOBs reprogramming cell did not pass through intermediate pluripotent cell types ο Feasible cell based therapy under bone resorption condition ο Human fibroblast can also be converted into osteolast using vector encoding ο Osterix ο L-myc ο Oct4
- 22. Chemically induced ο Alternative of transcrioption factor mediated reprorgramming 12 chemical compounds for reprogramming ο Among these TG4-B inhibitor Alk5ill ο Resulting IOBs exhibits a degree calcium deposition ο Direct conversion of cell surrounding a fracture may be a viable approach for promoting bone formation
- 23. Advantage over the use of IPSCs ο IPSCs has numereous genomic aberration ο Under go changers in gene copy number during their passage and differentiation ο Enhance the risk of oncogenesis ο Proliferation of IPSCs uncontrolled state is similar to that of cancereous cell
- 24. Biosafety Issues ο Direct reprogramming not been fully demonstrated to date in clinical trials ο Introduction of viruses in human is generally consider not a viable option ο Neoplastic transformation or lead to inflamantory diseases and epigenetic abnormalities ο Fundamental problem with direct reprogramming is telomere shortenning
- 25. ο DNA damage ο Proportion of heterochromatin ο Nuclear organization ο Lack of the require cell type ο Limited proliferation ο Low expression of osteogenic genes
- 26. ο In vivo reprogramming method should be considered in an in vivo environment ο Controllable expression system should be considered for optional in vivo reprogramming induction
- 27. Conclusion ο Bone fracture caused by age related osteoporosis have become a very significant probblem ο Direct reprogramming of somatic cell into osteoblas represents a potential approach for the treatment of bone fractures in elederly individuals