Skip to main content
Top
Published in: Journal of Orthopaedic Science 4/2014

Open Access 01-07-2014 | Review Article

Regenerative medicine in orthopedics using cells, scaffold, and microRNA

Authors: Mitsuo Ochi, Tomoyuki Nakasa, Goki Kamei, Muhammad Andry Usman, Hussein El Mahmoud

Published in: Journal of Orthopaedic Science | Issue 4/2014

Login to get access

Abstract

Cells, scaffold, and growth factors are crucially important in regenerative medicine and tissue engineering. Progress in science and technology has enabled development of these three factors, with basic research being applied clinically. In the past decade, we have investigated tissue regeneration in animal models of musculoskeletal disorders by using cells, scaffold, and delivery systems which has been relatively easy to apply and develop in clinical settings. Moreover, microRNA (miRNA), which are important in biological processes and in the pathogenesis of human diseases, have been used in research on regenerative medicine. For the cell source, we focused on mesenchymal stem cells (MSC) and CD34+ and CD133+ cells as endothelial progenitor cells for regeneration of musculoskeletal organs. These cells are accessible and safe. For less invasive and more effective therapy, we developed a novel cell-delivery system using magnetic force to accumulate cells at a desired site. Furthermore, administration of synthetic miRNA could enhance tissue regeneration. In our studies, use of these cells combined with a cell-delivery system, miRNA, scaffold, and cytokines has led to effective regeneration of musculoskeletal tissues including cartilage, bone, ligaments, muscle, peripheral nerves, and spinal cord. The current and future objective is more effective and less invasive cell-based therapy with spatial control of transplanted cells by use of an external magnetic force. Analysis of efficiency, safety, and the mechanism of tissue regeneration by cells, scaffold, and miRNA will lead to more promising regenerative medicine, involving the development of a new generation of therapy. This review will focus on our regenerative medicine research, which focuses on clinical application of cells, scaffold, and miRNA.
Literature
1.
2.
go back to reference Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663–76.PubMedCrossRef Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663–76.PubMedCrossRef
3.
go back to reference Ochi M. Shinya Yamanaka’s 2012 nobel prize and the radical change in orthopedic strategy thanks to his discovery of iPS cells. Acta Orthop. 2013;84(1):1–3.PubMedCentralPubMedCrossRef Ochi M. Shinya Yamanaka’s 2012 nobel prize and the radical change in orthopedic strategy thanks to his discovery of iPS cells. Acta Orthop. 2013;84(1):1–3.PubMedCentralPubMedCrossRef
4.
5.
go back to reference Prockop DJ. Marrow stromal cells as stem cells for nonhematopoietic tissues. Science. 1997;276(5309):71–4.PubMedCrossRef Prockop DJ. Marrow stromal cells as stem cells for nonhematopoietic tissues. Science. 1997;276(5309):71–4.PubMedCrossRef
6.
go back to reference Thery C, Ostrowski M, Segura E. Membrane vesicles as conveyors of immune responses. Nat Rev Immunol. 2009;9(8):581–93.PubMedCrossRef Thery C, Ostrowski M, Segura E. Membrane vesicles as conveyors of immune responses. Nat Rev Immunol. 2009;9(8):581–93.PubMedCrossRef
7.
go back to reference Lai RC, Arslan F, Lee MM, Sze NS, Choo A, Chen TS, Salto-Tellez M, Timmers L, Lee CN, El Oakley RM, Pasterkamp G, de Kleijn DP, Lim SK. Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res. 2010;4(3):214–22.PubMedCrossRef Lai RC, Arslan F, Lee MM, Sze NS, Choo A, Chen TS, Salto-Tellez M, Timmers L, Lee CN, El Oakley RM, Pasterkamp G, de Kleijn DP, Lim SK. Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res. 2010;4(3):214–22.PubMedCrossRef
8.
go back to reference Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM. Isolation of putative progenitor endothelial cells for angiogenesis. Science. 1997;275(5302):964–7.PubMedCrossRef Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM. Isolation of putative progenitor endothelial cells for angiogenesis. Science. 1997;275(5302):964–7.PubMedCrossRef
9.
go back to reference Kobayashi T, Ochi M, Yanada S, Ishikawa M, Adachi N, Deie M, Arihiro K. A novel cell delivery system using magnetically labeled mesenchymal stem cells and an external magnetic device for clinical cartilage repair. Arthoscopy. 2008;24(1):69–76.CrossRef Kobayashi T, Ochi M, Yanada S, Ishikawa M, Adachi N, Deie M, Arihiro K. A novel cell delivery system using magnetically labeled mesenchymal stem cells and an external magnetic device for clinical cartilage repair. Arthoscopy. 2008;24(1):69–76.CrossRef
10.
go back to reference Kamei G, Kobayashi T, Ohkawa S, Kongcharoensombat W, Adachi N, Takazawa K, Shibuya H, Deie M, Hattori K, Goldberg JL, Ochi M. Articular cartilage repair with magnetic mesenchymal stem cells. Am J Sports Med. 2013;41(6):1255–64.PubMedCrossRef Kamei G, Kobayashi T, Ohkawa S, Kongcharoensombat W, Adachi N, Takazawa K, Shibuya H, Deie M, Hattori K, Goldberg JL, Ochi M. Articular cartilage repair with magnetic mesenchymal stem cells. Am J Sports Med. 2013;41(6):1255–64.PubMedCrossRef
12.
13.
go back to reference Murata K, Yoshitomi H, Tanida S, Ishikawa M, Nishitani K, Ito H, Nakamura T. Plasma and synovial fluid microRNA as potential biomarkers of rheumatoid arthritis and osteoarthritis. Arthritis Res Ther. 2010;12(3):R86.PubMedCentralPubMedCrossRef Murata K, Yoshitomi H, Tanida S, Ishikawa M, Nishitani K, Ito H, Nakamura T. Plasma and synovial fluid microRNA as potential biomarkers of rheumatoid arthritis and osteoarthritis. Arthritis Res Ther. 2010;12(3):R86.PubMedCentralPubMedCrossRef
14.
go back to reference Uchio Y, Ochi M, Matsusaki M, Kurioka H, Katsube K. Human chondrocyte proliferation and matrix synthesis cultured in atelocollagen gel. J Biomed Mater Res A. 2000;50(2):138–43.CrossRef Uchio Y, Ochi M, Matsusaki M, Kurioka H, Katsube K. Human chondrocyte proliferation and matrix synthesis cultured in atelocollagen gel. J Biomed Mater Res A. 2000;50(2):138–43.CrossRef
15.
go back to reference Minakuchi Y, Takeshita F, Kosaka N, Sasaki H, Yamamoto Y, Kouno M, Honma K, Nagahara S, Hanai S, Sano A, Kato T, Terada M, Ochiya T. Atelocollagen-mediated synthetic small interfering RNA delivery for effective gene silencing in vitro and in vivo. Nucleic Acids Res. 2004;32(13):e109.PubMedCentralPubMedCrossRef Minakuchi Y, Takeshita F, Kosaka N, Sasaki H, Yamamoto Y, Kouno M, Honma K, Nagahara S, Hanai S, Sano A, Kato T, Terada M, Ochiya T. Atelocollagen-mediated synthetic small interfering RNA delivery for effective gene silencing in vitro and in vivo. Nucleic Acids Res. 2004;32(13):e109.PubMedCentralPubMedCrossRef
16.
go back to reference Tamai N, Myoui A, Tomita T, Nakase T, Tanaka J, Ochi T, Yosikawa H. Novel hydroxyapatite ceramics with an interconnective porus structure exhibit superior osteoconduction in vivo. J Biomed Mater Res. 2001;59(1):110–7.CrossRef Tamai N, Myoui A, Tomita T, Nakase T, Tanaka J, Ochi T, Yosikawa H. Novel hydroxyapatite ceramics with an interconnective porus structure exhibit superior osteoconduction in vivo. J Biomed Mater Res. 2001;59(1):110–7.CrossRef
17.
go back to reference Kawasaki K, Ochi M, Uchio Y, Adachi N, Matsusaki M. Hyaluronic acid enhances proliferation and chondroitin sulfate synthesis in cultured chondrocytes embedded in collagen gels. J Cell Physiol. 1999;179(2):142–8.PubMedCrossRef Kawasaki K, Ochi M, Uchio Y, Adachi N, Matsusaki M. Hyaluronic acid enhances proliferation and chondroitin sulfate synthesis in cultured chondrocytes embedded in collagen gels. J Cell Physiol. 1999;179(2):142–8.PubMedCrossRef
18.
go back to reference Brittberg M, Lindahl A, Nilsson A, Ohlsson C, Isaksson O, Peterson L. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Eng J Med. 1994;331(14):889–95.CrossRef Brittberg M, Lindahl A, Nilsson A, Ohlsson C, Isaksson O, Peterson L. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Eng J Med. 1994;331(14):889–95.CrossRef
19.
go back to reference Ochi M, Uchio Y, Kawasaki K, Wakitani S, Iwasa J. Transplantation of cartilage-like tissue made by tissue engineering in the treatment of cartilage defects of the knee. J Bone Joint Surg Br. 2002;84(4):571–8.PubMedCrossRef Ochi M, Uchio Y, Kawasaki K, Wakitani S, Iwasa J. Transplantation of cartilage-like tissue made by tissue engineering in the treatment of cartilage defects of the knee. J Bone Joint Surg Br. 2002;84(4):571–8.PubMedCrossRef
20.
go back to reference Ito Y, Ochi M, Adachi N, Sugawara K, Yanada S, Ikada Y, Ronakorn P. Repair of osteochondral defect with tissue-engineered chondral plug in a rabbit model. Arthroscopy. 2005;21(10):1155–63.PubMedCrossRef Ito Y, Ochi M, Adachi N, Sugawara K, Yanada S, Ikada Y, Ronakorn P. Repair of osteochondral defect with tissue-engineered chondral plug in a rabbit model. Arthroscopy. 2005;21(10):1155–63.PubMedCrossRef
21.
go back to reference Nishimori M, Deie M, Kanaya A, Exham H, Adachi N, Ochi M. Repair of chronic osteochondral defects in the rat. J Bone Joint Surg Br. 2006;88(9):1236–44.PubMedCrossRef Nishimori M, Deie M, Kanaya A, Exham H, Adachi N, Ochi M. Repair of chronic osteochondral defects in the rat. J Bone Joint Surg Br. 2006;88(9):1236–44.PubMedCrossRef
22.
go back to reference Agung M, Ochi M, Yanada S, Adachi N, Izuta Y, Yamasaki T, Toda K. Mobilization of bone marrow-derived mesenchymal stem cells into the injured tissues after intraarticular injection and their contribution to tissue regeneration. Knee Surg Sports Traumatol Arthrosc. 2006;14(12):1307–14.PubMedCrossRef Agung M, Ochi M, Yanada S, Adachi N, Izuta Y, Yamasaki T, Toda K. Mobilization of bone marrow-derived mesenchymal stem cells into the injured tissues after intraarticular injection and their contribution to tissue regeneration. Knee Surg Sports Traumatol Arthrosc. 2006;14(12):1307–14.PubMedCrossRef
23.
go back to reference Ito Y, Tanaka N, Fujimoto Y, Yasunaga Y, Ishida O, Agung M, Ochi M. Bone formation using interconnected porous calcium hydroxyapatite ceramic hybridized with cultured marrow stromal stem cells derived from Green rat. J Biomed Mater Res. 2004;69A(3):454–61.CrossRef Ito Y, Tanaka N, Fujimoto Y, Yasunaga Y, Ishida O, Agung M, Ochi M. Bone formation using interconnected porous calcium hydroxyapatite ceramic hybridized with cultured marrow stromal stem cells derived from Green rat. J Biomed Mater Res. 2004;69A(3):454–61.CrossRef
24.
go back to reference Oshima S, Ishikawa M, Mochizuki Y, Kobayashi T, Yasunaga Y, Ochi M. Enhancement of bone formation in an experimental bony defect using ferumoxide-labelled mesenchymal stromal cells and a magnetic targeting system. J Bone Joint Surg Br. 2010;92(11):1606–13.PubMedCrossRef Oshima S, Ishikawa M, Mochizuki Y, Kobayashi T, Yasunaga Y, Ochi M. Enhancement of bone formation in an experimental bony defect using ferumoxide-labelled mesenchymal stromal cells and a magnetic targeting system. J Bone Joint Surg Br. 2010;92(11):1606–13.PubMedCrossRef
25.
go back to reference Kodama A, Kamei G, Kongcharoensombat W, Ohkawa S, Nakabayashi A, Ochi M. In vivo bioluminescence imaging of transplanted bone marrow mesenchymal stromal cells using a magnetic delivery system in a rat fracture model. J Bone Joint Surg Br. 2012;94(7):998–1006.PubMedCrossRef Kodama A, Kamei G, Kongcharoensombat W, Ohkawa S, Nakabayashi A, Ochi M. In vivo bioluminescence imaging of transplanted bone marrow mesenchymal stromal cells using a magnetic delivery system in a rat fracture model. J Bone Joint Surg Br. 2012;94(7):998–1006.PubMedCrossRef
26.
go back to reference Nagineni CN, Amiel D, Green MH, Berchuck M, Akeson WH. Characterization of the intrinsic properties of the anterior cruciate and medial collateral ligament cells. J Orthop Res. 1992;10(4):465–75.PubMedCrossRef Nagineni CN, Amiel D, Green MH, Berchuck M, Akeson WH. Characterization of the intrinsic properties of the anterior cruciate and medial collateral ligament cells. J Orthop Res. 1992;10(4):465–75.PubMedCrossRef
27.
go back to reference Kanaya A, Deie M, Adachi N, Nishimori M, Yanada S, Ochi M. Intra-articular injection of mesenchymal stromal cells in partially torn anterior cruciate ligaments in a rat model. Arthroscopy. 2007;23(6):610–7.PubMedCrossRef Kanaya A, Deie M, Adachi N, Nishimori M, Yanada S, Ochi M. Intra-articular injection of mesenchymal stromal cells in partially torn anterior cruciate ligaments in a rat model. Arthroscopy. 2007;23(6):610–7.PubMedCrossRef
28.
go back to reference Shoji T, Nakasa T, Yamasaki K, Kodama A, Miyaki S, Niimoto T, Ohuhara A, Kamei N, Adachi N, Ochi M. The effect of intra-articular injection of microRNA-210 on ligament healing in a rat model. Am J Sports Med. 2012;40(11):2470–8.PubMedCrossRef Shoji T, Nakasa T, Yamasaki K, Kodama A, Miyaki S, Niimoto T, Ohuhara A, Kamei N, Adachi N, Ochi M. The effect of intra-articular injection of microRNA-210 on ligament healing in a rat model. Am J Sports Med. 2012;40(11):2470–8.PubMedCrossRef
29.
go back to reference Natsu K, Ochi M, Mochizuki Y, Hachisuka H, Yanada S, Yasunaga Y. Allogenic bone marrow-derived mesenchymal stromal cells promote the regeneration of injured skeletal muscle without differentiation into myofibers. Tissue Eng. 2004;10(7–8):1093–112.PubMedCrossRef Natsu K, Ochi M, Mochizuki Y, Hachisuka H, Yanada S, Yasunaga Y. Allogenic bone marrow-derived mesenchymal stromal cells promote the regeneration of injured skeletal muscle without differentiation into myofibers. Tissue Eng. 2004;10(7–8):1093–112.PubMedCrossRef
30.
go back to reference Shi M, Ishikawa M, Kamei N, Nakasa T, Adachi N, Deie M, Asahara T, Ochi M. Acceleration of skeletal muscle regeneration in a rat skeletal muscle injury model by local injection of human peripheral blood-derived CD133-positive cells. Stem Cells. 2009;27(4):949–60.PubMedCrossRef Shi M, Ishikawa M, Kamei N, Nakasa T, Adachi N, Deie M, Asahara T, Ochi M. Acceleration of skeletal muscle regeneration in a rat skeletal muscle injury model by local injection of human peripheral blood-derived CD133-positive cells. Stem Cells. 2009;27(4):949–60.PubMedCrossRef
31.
go back to reference Ohkawa S, Kamei N, Kamei G, Shi M, Adachi N, Deie M, Ochi M. Magnetic targeting of human peripheral blood CD133+ cells for skeletal muscle regeneration. Tissue Eng Part C Methods. 2013;19(8):631–41.PubMedCrossRef Ohkawa S, Kamei N, Kamei G, Shi M, Adachi N, Deie M, Ochi M. Magnetic targeting of human peripheral blood CD133+ cells for skeletal muscle regeneration. Tissue Eng Part C Methods. 2013;19(8):631–41.PubMedCrossRef
32.
go back to reference Nakasa T, Ishikawa M, Shi M, Shibuya H, Adachi N, Ochi M. Acceleration of muscle regeneration by local injection of muscle-specific microRNA in rat skeletal muscle injury model. J Cell Mol Med. 2010;14(10):2495–505.PubMedCrossRef Nakasa T, Ishikawa M, Shi M, Shibuya H, Adachi N, Ochi M. Acceleration of muscle regeneration by local injection of muscle-specific microRNA in rat skeletal muscle injury model. J Cell Mol Med. 2010;14(10):2495–505.PubMedCrossRef
33.
go back to reference Kijima Y, Ishikawa M, Sunagawa T, Nakanishi K, Kamei N, Yamada K, Tanaka N, Kawamata S, Asahara T, Ochi M. Regeneration of peripheral nerve after transplantation of CD133+ cells derived from human peripheral blood. J Neurosurg. 2009;110(4):758–67.PubMedCrossRef Kijima Y, Ishikawa M, Sunagawa T, Nakanishi K, Kamei N, Yamada K, Tanaka N, Kawamata S, Asahara T, Ochi M. Regeneration of peripheral nerve after transplantation of CD133+ cells derived from human peripheral blood. J Neurosurg. 2009;110(4):758–67.PubMedCrossRef
34.
go back to reference Masuda H, Iwasaki H, Kawamoto A, Akimaru H, Ishikawa M, Ii M, Shizuno T, Sato A, Ito R, Horii M, Ishida H, Kato S, Asahara T. Development of serum-free quality and quantity control culture of colony forming endothelial progenitor cell expansion for vasculogenesis. Stem Cells Trans Med. 2012;1(2):160–71.CrossRef Masuda H, Iwasaki H, Kawamoto A, Akimaru H, Ishikawa M, Ii M, Shizuno T, Sato A, Ito R, Horii M, Ishida H, Kato S, Asahara T. Development of serum-free quality and quantity control culture of colony forming endothelial progenitor cell expansion for vasculogenesis. Stem Cells Trans Med. 2012;1(2):160–71.CrossRef
35.
go back to reference Ohtsubo S, Ishikawa M, Kamei N, Kijima Y, Suzuki O, Sunagawa T, Higashi Y, Masuda H, Asahara T, Ochi M. The therapeutic potential of ex vivo expanded CD133+ cells derived from human peripheral blood for peripheral nerve injuries. J Neurosurg. 2012;117(4):787–94.PubMedCrossRef Ohtsubo S, Ishikawa M, Kamei N, Kijima Y, Suzuki O, Sunagawa T, Higashi Y, Masuda H, Asahara T, Ochi M. The therapeutic potential of ex vivo expanded CD133+ cells derived from human peripheral blood for peripheral nerve injuries. J Neurosurg. 2012;117(4):787–94.PubMedCrossRef
36.
go back to reference Sasaki H, Ishikawa M, Tanaka N, Nakanishi K, Kamei N, Asahara T, Ochi M. Administration of human peripheral blood-derived CD133+ cells accelerates functional recovery in a rat spinal cord injury model. Spine. 2009;34(3):249–54.PubMedCrossRef Sasaki H, Ishikawa M, Tanaka N, Nakanishi K, Kamei N, Asahara T, Ochi M. Administration of human peripheral blood-derived CD133+ cells accelerates functional recovery in a rat spinal cord injury model. Spine. 2009;34(3):249–54.PubMedCrossRef
37.
go back to reference Kamei N, Kwon SM, Ishikawa M, Ii M, Nakanishi K, Yamada K, Hozumi K, Kawamoto A, Ochi M, Asahara T. Endothelial progenitor cells promote astrogliosis following spinal cord injury through Jagged1-dependent Notch signaling. J Neurotrauma. 2012;29(9):1758–69.PubMedCrossRef Kamei N, Kwon SM, Ishikawa M, Ii M, Nakanishi K, Yamada K, Hozumi K, Kawamoto A, Ochi M, Asahara T. Endothelial progenitor cells promote astrogliosis following spinal cord injury through Jagged1-dependent Notch signaling. J Neurotrauma. 2012;29(9):1758–69.PubMedCrossRef
38.
go back to reference Kamei N, Kwon SM, Alev C, Nakanishi K, Yamada K, Masuda H, Ishikawa M, Kawamoto A, Ochi M, Asahara T. Ex-vivo expanded human blood-derived CD133+ cells promote repair of injured spinal cord. J Neurol Sci. 2013;328(1–2):41–50.PubMedCrossRef Kamei N, Kwon SM, Alev C, Nakanishi K, Yamada K, Masuda H, Ishikawa M, Kawamoto A, Ochi M, Asahara T. Ex-vivo expanded human blood-derived CD133+ cells promote repair of injured spinal cord. J Neurol Sci. 2013;328(1–2):41–50.PubMedCrossRef
39.
go back to reference Fujioka Y, Tanaka N, Nakanishi K, Kamei N, Nakamae T, Izumi B, Ohta R, Ochi M. Magnetic field-based delivery of human CD133+ cells promotes functional recovery after rat spinal cord injury. Spine. 2012;37(13):E768–77.PubMedCrossRef Fujioka Y, Tanaka N, Nakanishi K, Kamei N, Nakamae T, Izumi B, Ohta R, Ochi M. Magnetic field-based delivery of human CD133+ cells promotes functional recovery after rat spinal cord injury. Spine. 2012;37(13):E768–77.PubMedCrossRef
Metadata
Title
Regenerative medicine in orthopedics using cells, scaffold, and microRNA
Authors
Mitsuo Ochi
Tomoyuki Nakasa
Goki Kamei
Muhammad Andry Usman
Hussein El Mahmoud
Publication date
01-07-2014
Publisher
Springer Japan
Published in
Journal of Orthopaedic Science / Issue 4/2014
Print ISSN: 0949-2658
Electronic ISSN: 1436-2023
DOI
https://doi.org/10.1007/s00776-014-0575-6

Other articles of this Issue 4/2014

Journal of Orthopaedic Science 4/2014 Go to the issue