间充质干细胞与骨折愈合
Mesenchymal Stem Cells and Fracture Healing
DOI: 10.12677/jcpm.2024.34389, PDF,    科研立项经费支持
作者: 陈晓峰*, 孙明启#：内蒙古医科大学第二附属医院创伤骨科，内蒙古 呼和浩特市
关键词: 间充质干细胞；骨折愈合；Mesenchymal Stem Cells； Fracture Healing
摘要: 间充质干细胞(MSCs)起源于胚胎的中胚层，具有在体内外分化为骨骼、软骨等多种组织的能力。这些干细胞在修复和再生医学中具有显著的应用潜力，尤其是在心脏、肝脏和皮肤损伤的修复。在骨科领域，MSCs能够促进骨折愈合，但其机制仍不完全明确。近年的研究表明，MSCs通过调节炎症反应、免疫系统和血管新生，以及促进成骨分化，对骨折愈合的各个阶段产生影响。通过分泌生长因子、外泌体和其他生物活性物质，这些细胞激活多条信号通路，加速骨折的愈合过程，并显示出在骨组织修复中的重要性。
Abstract: Mesenchymal stem cells (MSCs) originate from the mesoderm of the embryo and have the ability to differentiate into various tissues such as bone and cartilage in vitro and in vivo. These stem cells have significant potential for applications in restorative and regenerative medicine, especially in the repair of heart, liver, and skin damage. In orthopedics, MSCs can promote fracture healing, but the mechanism is still not fully understood. Recent studies have shown that MSCs have an impact on all stages of fracture healing by modulating the inflammatory response, immune system and angiogenesis, and promoting osteogenic differentiation. By secreting growth factors, exosomes, and other bioactive substances, these cells activate multiple signaling pathways, accelerate the healing process of fractures, and show importance in bone tissue repair.
文章引用：陈晓峰, 孙明启. 间充质干细胞与骨折愈合[J]. 临床个性化医学, 2024, 3(4): 2743-2751. https://doi.org/10.12677/jcpm.2024.34389

参考文献

[1] Einhorn, T.A. and Gerstenfeld, L.C. (2014) Fracture Healing: Mechanisms and Interventions. Nature Reviews Rheumatology, 11, 45-54. [Google Scholar] [CrossRef] [PubMed]
[2] Bordukalo-Nikšić, T., Kufner, V. and Vukičević, S. (2022) The Role of Bmps in the Regulation of Osteoclasts Resorption and Bone Remodeling: From Experimental Models to Clinical Applications. Frontiers in Immunology, 13, Article 869422. [Google Scholar] [CrossRef] [PubMed]
[3] Hankenson, K.D., Gagne, K. and Shaughnessy, M. (2015) Extracellular Signaling Molecules to Promote Fracture Healing and Bone Regeneration. Advanced Drug Delivery Reviews, 94, 3-12. [Google Scholar] [CrossRef] [PubMed]
[4] Bragdon, B.C. and Bahney, C.S. (2018) Origin of Reparative Stem Cells in Fracture Healing. Current Osteoporosis Reports, 16, 490-503. [Google Scholar] [CrossRef] [PubMed]
[5] Vester, H., Huber-Lang, M.S., Kida, Q., Scola, A., van Griensven, M., Gebhard, F., et al. (2014) The Immune Response after Fracture Trauma Is Different in Old Compared to Young Patients. Immunity & Ageing, 11, Article No. 20. [Google Scholar] [CrossRef] [PubMed]
[6] Gibon, E., Lu, L. and Goodman, S.B. (2016) Aging, Inflammation, Stem Cells, and Bone Healing. Stem Cell Research & Therapy, 7, Article No. 44. [Google Scholar] [CrossRef] [PubMed]
[7] Maruyama, M., Rhee, C., Utsunomiya, T., Zhang, N., Ueno, M., Yao, Z., et al. (2020) Modulation of the Inflammatory Response and Bone Healing. Frontiers in Endocrinology, 11, Article No. 386. [Google Scholar] [CrossRef] [PubMed]
[8] Park, D., Spencer, J.A., Koh, B.I., Kobayashi, T., Fujisaki, J., Clemens, T.L., et al. (2012) Endogenous Bone Marrow MSCs Are Dynamic, Fate-Restricted Participants in Bone Maintenance and Regeneration. Cell Stem Cell, 10, 259-272. [Google Scholar] [CrossRef] [PubMed]
[9] Ishikawa, M., Ito, H., Kitaori, T., Murata, K., Shibuya, H., Furu, M., et al. (2014) MCP/CCR2 Signaling Is Essential for Recruitment of Mesenchymal Progenitor Cells during the Early Phase of Fracture Healing. PLOS ONE, 9, e104954. [Google Scholar] [CrossRef] [PubMed]
[10] Toupadakis, C.A., Granick, J.L., Sagy, M., Wong, A., Ghassemi, E., Chung, D., et al. (2013) Mobilization of Endogenous Stem Cell Populations Enhances Fracture Healing in a Murine Femoral Fracture Model. Cytotherapy, 15, 1136-1147. [Google Scholar] [CrossRef] [PubMed]
[11] Ho, C., Sanghani, A., Hua, J., Coathup, M., Kalia, P. and Blunn, G. (2015) Mesenchymal Stem Cells with Increased Stromal Cell-Derived Factor 1 Expression Enhanced Fracture Healing. Tissue Engineering Part A, 21, 594-602. [Google Scholar] [CrossRef] [PubMed]
[12] Wei, F., Chow, S., Leung, K., Qin, J., Guo, A., Yu, O., et al. (2016) Low-magnitude High-Frequency Vibration Enhanced Mesenchymal Stem Cell Recruitment in Osteoporotic Fracture Healing through the SDF-1/CXCR4 Pathway. European Cells and Materials, 31, 341-354. [Google Scholar] [CrossRef] [PubMed]
[13] Wei, F., Leung, K., Li, G., Qin, J., Chow, S.K., Huang, S., et al. (2014) Low Intensity Pulsed Ultrasound Enhanced Mesenchymal Stem Cell Recruitment through Stromal Derived Factor-1 Signaling in Fracture Healing. PLOS ONE, 9, e106722. [Google Scholar] [CrossRef] [PubMed]
[14] Ye, D., Chen, C., Wang, Q., Zhang, Q., Li, S. and Liu, H. (2020) Short-Wave Enhances Mesenchymal Stem Cell Recruitment in Fracture Healing by Increasing HIF-1 in Callus. Stem Cell Research & Therapy, 11, Article No. 382. [Google Scholar] [CrossRef] [PubMed]
[15] Yang, B., Lin, X., Tan, J., She, X., Liu, Y. and Kuang, H. (2016) Root Bark of Sambucus williamsii Hance Promotes Rat Femoral Fracture Healing by the BMP-2/Runx2 Signaling Pathway. Journal of Ethnopharmacology, 191, 107-114. [Google Scholar] [CrossRef] [PubMed]
[16] Feigenson, M., Jonason, J.H., Shen, J., Loiselle, A.E., Awad, H.A. and O’Keefe, R.J. (2019) Inhibition of the Prostaglandin EP-1 Receptor in Periosteum Progenitor Cells Enhances Osteoblast Differentiation and Fracture Repair. Annals of Biomedical Engineering, 48, 927-939. [Google Scholar] [CrossRef] [PubMed]
[17] Zhang, M., Ho, H., Sheu, T., Breyer, M.D., Flick, L.M., Jonason, J.H., et al. (2010) EP1−/− Mice Have Enhanced Osteoblast Differentiation and Accelerated Fracture Repair. Journal of Bone and Mineral Research, 26, 792-802. [Google Scholar] [CrossRef] [PubMed]
[18] Herrmann, M., Stanić, B., Hildebrand, M., Alini, M. and Verrier, S. (2019) In Vitro Simulation of the Early Proinflammatory Phase in Fracture Healing Reveals Strong Immunomodulatory Effects of CD146‐Positive Mesenchymal Stromal Cells. Journal of Tissue Engineering and Regenerative Medicine, 13, 1466-1481. [Google Scholar] [CrossRef] [PubMed]
[19] Kovach, T.K., Dighe, A.S., Lobo, P.I. and Cui, Q. (2015) Interactions between MSCs and Immune Cells: Implications for Bone Healing. Journal of Immunology Research, 2015, Article ID: 752510. [Google Scholar] [CrossRef] [PubMed]
[20] Wang, C., Yang, H., Hsu, H., Chen, L., Tsai, C., Tsai, K., et al. (2011) Mesenchymal Stem Cell-Conditioned Medium Facilitates Angiogenesis and Fracture Healing in Diabetic Rats. Journal of Tissue Engineering and Regenerative Medicine, 6, 559-569. [Google Scholar] [CrossRef] [PubMed]
[21] Wang, K., Zhou, C., Li, L., Dai, C., Wang, Z., Zhang, W., et al. (2022) Aucubin Promotes Bone-Fracture Healing via the Dual Effects of Anti-Oxidative Damage and Enhancing Osteoblastogenesis of hBM-MSCs. Stem Cell Research & Therapy, 13, Article No. 424. [Google Scholar] [CrossRef] [PubMed]
[22] Carroll, S.H., Wigner, N.A., Kulkarni, N., Johnston-Cox, H., Gerstenfeld, L.C. and Ravid, K. (2012) A2B Adenosine Receptor Promotes Mesenchymal Stem Cell Differentiation to Osteoblasts and Bone Formation in Vivo. Journal of Biological Chemistry, 287, 15718-15727. [Google Scholar] [CrossRef] [PubMed]
[23] Hu, D., Gu, X., Si, W., Qin, W., Jiao, J. and Hao, Y. (2019) Biosynthesis of Silver Nanoparticles Using Bauhinia Acuminate Flower Extract and Their Effect to Promote Osteogenesis of Mscs and Improve Meniscus Injury Healing. Journal of Photochemistry and Photobiology B: Biology, 197, Article ID: 111536. [Google Scholar] [CrossRef] [PubMed]
[24] Zhang, W., Xue, D., Yin, H., Wang, S., Li, C., Chen, E., et al. (2016) Overexpression of HSPA1A Enhances the Osteogenic Differentiation of Bone Marrow Mesenchymal Stem Cells via Activation of the Wnt/β-Catenin Signaling Pathway. Scientific Reports, 6, Article No. 27622. [Google Scholar] [CrossRef] [PubMed]
[25] Lu, X., Li, J., Zhou, B., Lu, X., Li, W. and Ouyang, J. (2023) Taohong Siwu Decoction Enhances Human Bone Marrow Mesenchymal Stem Cells Proliferation, Migration and Osteogenic Differentiation via VEGF-FAK Signaling in Vitro. Journal of Ethnopharmacology, 307, Article ID: 116203. [Google Scholar] [CrossRef] [PubMed]
[26] Jiao, J., Feng, G., Wu, M., Wang, Y., Li, R. and Liu, J. (2020) MiR‐140‐5p Promotes Osteogenic Differentiation of Mouse Embryonic Bone Marrow Mesenchymal Stem Cells and Post‐Fracture Healing of Mice. Cell Biochemistry and Function, 38, 1152-1160. [Google Scholar] [CrossRef] [PubMed]
[27] Cui, Y., Huang, R., Wang, Y., Zhu, L. and Zhang, X. (2018) Down-Regulation of LGR6 Promotes Bone Fracture Recovery Using Bone Marrow Stromal Cells. Biomedicine & Pharmacotherapy, 99, 629-637. [Google Scholar] [CrossRef] [PubMed]
[28] Guo, P.Y., Wu, L.F., Xiao, Z.Y., et al. (2019) Knockdown of MiR-140-5 Promotes Osteogenesis of Adipose-Derived Mesenchymal Stem Cells by Targeting TLR4 and BMP2 and Promoting Fracture Healing in the Atrophic Nonunion Rat Model. European Review for Medical and Pharmacological Sciences, 23, 2112-2124.
[29] Xie, H., Liu, M., Jin, Y., Lin, H., Zhang, Y. and Zheng, S. (2020) MiR-1323 Suppresses Bone Mesenchymal Stromal Cell Osteogenesis and Fracture Healing via Inhibiting BMP4/SMAD4 Signaling. Journal of Orthopaedic Surgery and Research, 15, Article No. 237. [Google Scholar] [CrossRef] [PubMed]
[30] Yang, G., Liu, K., Ma, S. and Qi, P. (2024) PPARγ Inhibition Promotes Osteogenic Differentiation of Bone Marrow Mesenchymal Stem Cells and Fracture Healing. Journal of Cellular Biochemistry, 125, e30568. [Google Scholar] [CrossRef] [PubMed]
[31] Yoshizuka, M., Nakasa, T., Kawanishi, Y., Hachisuka, S., Furuta, T., Miyaki, S., et al. (2016) Inhibition of Microrna-222 Expression Accelerates Bone Healing with Enhancement of Osteogenesis, Chondrogenesis, and Angiogenesis in a Rat Refractory Fracture Model. Journal of Orthopaedic Science, 21, 852-858. [Google Scholar] [CrossRef] [PubMed]
[32] Wang, C., Wang, X., Cheng, H. and Fang, J. (2023) Mir‐22‐3p Facilitates Bone Marrow Mesenchymal Stem Cell Osteogenesis and Fracture Healing through the SOSTDC1‐PI3K/AKT Pathway. International Journal of Experimental Pathology, 105, 52-63. [Google Scholar] [CrossRef] [PubMed]
[33] Collette, N.M., Yee, C.S., Hum, N.R., Murugesh, D.K., Christiansen, B.A., Xie, L., et al. (2016) Sostdc1 Deficiency Accelerates Fracture Healing by Promoting the Expansion of Periosteal Mesenchymal Stem Cells. Bone, 88, 20-30. [Google Scholar] [CrossRef] [PubMed]
[34] Roberts, J.L., Kapfhamer, D., Devarapalli, V. and Drissi, H. (2024) IL-17RA Signaling in Prx1+ Mesenchymal Cells Influences Fracture Healing in Mice. International Journal of Molecular Sciences, 25, Article No. 3751. [Google Scholar] [CrossRef] [PubMed]
[35] Sivaraj, K.K., Majev, P., Jeong, H., Dharmalingam, B., Zeuschner, D., Schröder, S., et al. (2022) Mesenchymal Stromal Cell-Derived Septoclasts Resorb Cartilage during Developmental Ossification and Fracture Healing. Nature Communications, 13, Article No. 571. [Google Scholar] [CrossRef] [PubMed]
[36] Watanabe, Y., Harada, N., Sato, K., Abe, S., Yamanaka, K. and Matushita, T. (2016) Stem Cell Therapy: Is There a Future for Reconstruction of Large Bone Defects? Injury, 47, S47-S51. [Google Scholar] [CrossRef] [PubMed]
[37] Zhou, Y., Jiang, R., An, L., Wang, H., Cheng, S., Qiong, S., et al. (2017) Benzo[α]Pyrene Impedes Self-Renewal and Differentiation of Mesenchymal Stem Cells and Influences Fracture Healing. Science of the Total Environment, 587, 305-315. [Google Scholar] [CrossRef] [PubMed]
[38] Zhang, X., Chen, Y., Zhang, C., Zhang, X., Xia, T., Han, J., et al. (2020) Icariin Accelerates Fracture Healing via Activation of the Wnt1/β-Catenin Osteogenic Signaling Pathway. Current Pharmaceutical Biotechnology, 21, 1645-1653. [Google Scholar] [CrossRef] [PubMed]
[39] Zhao, X., Wang, Q., Wang, W. and Lu, S. (2024) Increased Neutrophil Extracellular Traps Caused by Diet‐Induced Obesity Delay Fracture Healing. The FASEB Journal, 38, e70126. [Google Scholar] [CrossRef] [PubMed]
[40] Cheng, S., Hu, X., Sun, K., Huang, Z., Zhao, Y., Sun, Y., et al. (2024) Local Application of Tanshinone IIA Protects Mesenchymal Stem Cells from Apoptosis and Promotes Fracture Healing in Ovariectomized Mice. Journal of Orthopaedic Surgery and Research, 19, Article No. 309. [Google Scholar] [CrossRef] [PubMed]
[41] Li, C., Wang, Q., Gu, X., Kang, Y., Zhang, Y., Hu, Y., et al. (2019) Porous Se@SiO2 Nanocomposite Promotes Migration and Osteogenic Differentiation of Rat Bone Marrow Mesenchymal Stem Cell to Accelerate Bone Fracture Healing in a Rat Model. International Journal of Nanomedicine, 14, 3845-3860. [Google Scholar] [CrossRef] [PubMed]
[42] Chen, X., Li, C., Zhao, J., Liu, Y., Zhao, Z., Wang, Z., et al. (2024) mPPTMP195 Nanoparticles Enhance Fracture Recovery through HDAC4 Nuclear Translocation Inhibition. Journal of Nanobiotechnology, 22, Article No. 261. [Google Scholar] [CrossRef] [PubMed]
[43] Wang, X., Wang, C., Gou, W., Xu, X., Wang, Y., Wang, A., et al. (2018) The Optimal Time to Inject Bone Mesenchymal Stem Cells for Fracture Healing in a Murine Model. Stem Cell Research & Therapy, 9, Article No. 272. [Google Scholar] [CrossRef] [PubMed]
[44] Zheng, S., Hu, G., Zheng, J., Li, Y. and Li, J. (2024) Osthole Accelerates Osteoporotic Fracture Healing by Inducing the Osteogenesis-Angiogenesis Coupling of BMSCs via the Wnt/β‐Catenin Pathway. Phytotherapy Research, 38, 4022-4035. [Google Scholar] [CrossRef] [PubMed]
[45] Zhang, H., Li, X., Liu, J., Lin, X., Pei, L., Boyce, B.F., et al. (2022) Proteasome Inhibition-Enhanced Fracture Repair Is Associated with Increased Mesenchymal Progenitor Cells in Mice. PLOS ONE, 17, e0263839. [Google Scholar] [CrossRef] [PubMed]
[46] Zhao, L., Xiang, S., Tang, C., Liu, W., Gao, J., Li, X., et al. (2024) Sclerostin Transduced Bone Marrow Mesenchymal Stem Cells Promote Fracture Healing in Rats through the Wnt/β-Catenin Signal Pathway. Stem Cells and Development, 33, 438-447. [Google Scholar] [CrossRef] [PubMed]