Application of Stem Cells for Bone Regeneration in Critical-Sized Defects
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Purpose of Review
To discuss tissue bioengineering for critical-sized bone defects. To review the current stem cells that are in use and to describe the importance of an animal model for studying critical-sized bone defects.
Bone marrow mesenchymal stem cells (MSCs) are well investigated. Recently, other sources of MSCs have been identified and studied in critical-sized bone defects. As for animal models, several have been used to evaluate the use of stem cells in promoting regeneration in critical-sized bone defects. This review specifically focuses on one of the most widely used and accepted models, the rodent calvarium.
Stem cell therapy is promising for bone regeneration, especially for critical-sized bone defects. Additional studies are needed to better understand both the properties and mechanisms of the different types of stem cells, and to develop animal models that mimic human biology.
KeywordsCritical-sized bone defects Bone regeneration Stem cells Mesenchymal stem cells Bone morphogenic protein BMP
Compliance with Ethical Standards
Conflict of Interest
All authors declare no conflicts of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major Importance
- 7.Govender S, Csimma C, Genant HK, Valentin-Opran A, Amit Y, Arbel R, et al. Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients. J Bone Joint Surg Am. 2002;84-A:2123–34.PubMedGoogle Scholar
- 8.Burkus JK, Transfeldt EE, Kitchel SH, Watkins RG, Balderston RA. Clinical and radiographic outcomes of anterior lumbar interbody fusion using recombinant human bone morphogenetic protein-2. Spine (Phila Pa 1976). 2002;27:2396–408.Google Scholar
- 9.Vaccaro AR, Anderson DG, Patel T, Fischgrund J, Truumees E, Herkowitz HN, et al. Comparison of OP-1 Putty (rhBMP-7) to iliac crest autograft for posterolateral lumbar arthrodesis: a minimum 2-year follow-up pilot study. Spine (Phila Pa 1976). 2005;30:2709–16.Google Scholar
- 11.Jones AL, Bucholz RW, Bosse MJ, Mirza SK, Lyon TR, Webb LX, et al. Recombinant human BMP-2 and allograft compared with autogenous bone graft for reconstruction of diaphyseal tibial fractures with cortical defects. A randomized, controlled trial. J Bone Joint Surg Am. 2006;88:1431–41.PubMedGoogle Scholar
- 12.de Peppo GM, Svensson S, Lenneras M, Synnergren J, Stenberg J, Strehl R, et al. Human embryonic mesodermal progenitors highly resemble human mesenchymal stem cells and display high potential for tissue engineering applications. Tissue Eng A. 2010;16:2161–82.Google Scholar
- 19.• Akutsu H, Nasu M, Morinaga S, Motoyama T, Homma N, Machida M, et al. In vivo maturation of human embryonic stem cell-derived teratoma over time. Regen Ther. 2016;5:31–9 This study performed in vivo tumorigenicity tests using teratoma formation and genome-wide sequencing analysis of undifferentiated hESCs.Google Scholar
- 20.•• Volarevic V, Markovic BS, Gazdic M, Volarevic A, Jovicic N, Arsenijevic N, et al. Ethical and safety issues of stem cell-based therapy. Int J Med Sci. 2018;15(1):36. In this review, the authors provided an overview of the most important ethical issues in stem cell therapy, as a contribution to the controversial debate about their clinical usage in regenerative and transplantation medicine–45.PubMedPubMedCentralGoogle Scholar
- 24.•• Si JW, Wang XD, Shen SG. Perinatal stem cells: a promising cell resource for tissue engineering of craniofacial bone. World J Stem Cells. 2015;7(1):149. In this review, the authors summarized the current achievements and obstacles in stem cell-based craniofacial bone regeneration and addressed the characteristics of various types of perinatal stem cells and their novel application in tissue engineering of craniofacial bone–59.PubMedPubMedCentralGoogle Scholar
- 26.•• Watanabe Y, Harada N, Sato K, Abe S, Yamanaka K, Matushita T. Stem cell therapy: is there a future for reconstruction of large bone defects? Injury. 2016;47:S47–51 Reviews the healing of large femur defects in rats by transplantation of “MSCs pre-differentiated in vitro into cartilage-forming chondrocytes”—mesenchymal stem cell-derived chondrocytes (MSC-DCs). PubMedGoogle Scholar
- 31.•• Oryan A, Kamali A, Moshiri A, Eslaminejad MB. Role of mesenchymal stem cells in bone regenerative medicine: what is the evidence? Cells Tissues Organs. 2017;204(2):59–83 In this review, recent advances in the mechanisms of MSC action and the delivery approaches in bone regenerative medicine were discussed. PubMedGoogle Scholar
- 36.• Barba M, Di Taranto G, Lattanzi W. Adipose-derived stem cell therapies for bone regeneration. Expert Opin Biol Ther. 2017;17(6):677–89 This review defines the state-of-the-art on adipose-derived stem cells (ASCs), encompassing the biological features that make them suitable for bone regenerative strategies, and to provide an update on existing preclinical and clinical applications.PubMedGoogle Scholar
- 37.•• Ercal P, Pekozer GG, Kose GT. Dental stem cells in bone tissue engineering: current overview and challenges. Adv Exp Med Biol. 2018 Mar 2. https://doi.org/10.1007/5584_2018_171 Evaluates the regenerative potential of periodontal ligament-derived stem cells (PDLSCs) and osteoblast differentiated from PDLSCs in comparison with bone marrow-derived mesenchymal stem cells (BMSCs) and pre-osteoblasts in calvarial defects. Google Scholar
- 44.• Nakajima K, Kunimatsu R, Ando K, Ando T, Hayashi Y, Kihara T, et al. Comparison of the bone regeneration ability between stem cells from human exfoliated deciduous teeth, human dental pulp stem cells and human bone marrow mesenchymal stem cells. Biochem Biophys Res Commun. 2018;497(3):876–82 The study demonstrated that stem cells from human exfoliated deciduous teeth (SHED) are one of the best candidates as a cell source for the reconstruction of alveolar cleft due to the bone regeneration ability with less surgical invasion.PubMedGoogle Scholar
- 46.•• Leyendecker Junior A, Gomes Pinheiro CC, Lazzaretti Fernandes T, Franco Bueno D. The use of human dental pulp stem cells for in vivo bone tissue engineering: a systematic review. J Tissue Eng. 2018;9:2041731417752766 Through a systematic review of the literature, the authors evaluated the efficacy of human dental pulp stem cells and stem cells from human exfoliated deciduous teeth (SHED) for bone regeneration.PubMedPubMedCentralGoogle Scholar
- 58.Moshaverinia A, Chen C, Xu X, Akiyama K, Ansari S, Zadeh HH, et al. Bone regeneration potential of stem cells derived from periodontal ligament or gingival tissue sources encapsulated in RGD-modified alginate scaffold. Tissue Eng A. 2014;20(3–4):611–21.Google Scholar
- 59.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.Google Scholar
- 61.•• Bastami F, Nazeman P, Moslemi H, Rezai Rad M, Sharifi K, Khojasteh A. Induced pluripotent stem cells as a new getaway for bone tissue engineering: a systematic review. Cell Prolif. 2017;50(2) According to the review, osteoinduced pluripotent stem cells (iPSCs) revealed osteogenic capability equal to or superior than that of MSCs.Google Scholar
- 62.Hayashi K, Ochiai-Shino H, Shiga T, Onodera S, Saito A, Shibahara T, et al. Transplantation of human-induced pluripotent stem cells carried by self-assembling peptide nanofiber hydrogel improves bone regeneration in rat calvarial bone defects. BDJ Open. 2016;2:15007.PubMedPubMedCentralGoogle Scholar
- 63.•• Li Y, Chen S-K, Li L, Qin L, Wang X-L, Lai Y-X. Bone defect animal models for testing efficacy of bone substitute biomaterials. J Orthop Translat. 2015;3:95–104 This review discusses the most available and commonly used bone defect animal models for testing specific substitute biomaterials.PubMedPubMedCentralGoogle Scholar
- 66.Schmitz JP, Hollinger JO. The critical size defect as an experimental model for craniomandibulofacial nonunions. Clin Orthop Relat Res. 1986. https://doi.org/10.1097/00003086-198604000-00036.
- 69.Henslee A, Spicer P, Yoon D, Nair M, Meretoja V, Witherel K, et al. Biodegradable composite scaffolds incorporating an intramedullary rod and delivering bone morphogenetic protein-2 for stabilization and bone regeneration in segmental long bone defects. Acta Biomater. 2011;7:3627–37.PubMedPubMedCentralGoogle Scholar
- 73.Meszaros LB, Usas A, Cooper GM, Huard J. Effect of host sex and sex hormones on muscle-derived stem cell-mediated bone formation and defect healing. Tissue Eng A. 2012;18:1751–9.Google Scholar
- 74.Behr B, Sorkin M, Lehnhardt M, Renda A, Longaker MT, Quarto N. A comparative analysis of the osteogenic effects of BMP-2, FGF-2, and VEGFA in a calvarial defect model. Tissue Eng A. 2012;18:1079–86.Google Scholar
- 77.Barnes GL, Einhorn TA. Enhancement of fracture healing with parathyroid hormone. Clin Rev Bone Miner Metab. 2006;4:269–76.Google Scholar
- 90.•• Ning B, Zhao Y, Buza JA, Li W, Wang W, Jia T. Surgically-induced mouse models in the study of bone regeneration: current models and future directions. Mol Med Rep. 2017;15:1017–23 The review introduces a classification of surgically induced mouse models in bone regeneration, evaluates the application and value of these models, and discusses the potential development of further innovations in this field in the future. PubMedPubMedCentralGoogle Scholar
- 93.• Liu Z, Yuan X, Fernandes G, Dziak R, Ionita CN, Li C, et al. The combination of nano-calcium sulfate/platelet rich plasma gel scaffold with BMP2 gene-modified mesenchymal stem cells promotes bone regeneration in rat critical sized calvarial defects. Stem Cell Res Ther. 2017. https://doi.org/10.1186/s13287-017-0574-6 This study shows that nano-calcium sulfate/platelet-rich plasma (nCS/PRP) scaffolds containing BMP2-modified MSCs successfully promote bone regeneration in critical-sized bone defects.