Research progress of Schwann cells regulating bone regeneration_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

WANG Xiaoyu , ZHANG Rui ^△ , YU Yifan ,  XU Jia ,  KANG Qinglin

Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, 200233, P. R. China;

Corresponding author：

XU Jia, Email: xujia0117@126.com; KANG Qinglin, Email: orthokang@163.com

Keywords：

Schwann cells; osteogenesis; vascularization; neurotrophic factor; growth factor; bone tissue engineering

DOI：

10.7507/1002-1892.202108153

Video：

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Objective To review the research progress on the role of Schwann cells in regulating bone regeneration. Methods The domestic and foreign literature about the behavior of Schwann cells related to bone regeneration, multiple tissue repair ability, nutritional effects of their neurotrophic factor network, and their application in bone tissue engineering was extensively reviewed. Results As a critical part of the peripheral nervous system, Schwann cells regulate the expression level of various neurotrophic factors and growth factors through the paracrine effect, and participates in the tissue regeneration and differentiation process of non-neural tissues such as blood vessels and bone, reflecting the nutritional effect of neural-vascular-bone integration. Conclusion Taking full advantage of the multipotent differentiation ability of Schwann cells in nerve, blood vessel, and bone tissue regeneration may provide novel insights for clinical application of tissue engineered bone.

Citation： WANG Xiaoyu, ZHANG Rui, YU Yifan, XU Jia, KANG Qinglin. Research progress of Schwann cells regulating bone regeneration. Chinese Journal of Reparative and Reconstructive Surgery, 2022, 36(2): 236-241. doi: 10.7507/1002-1892.202108153 Copy

1.	Fan J, Bi L, Jin D, et al. Microsurgical techniques used to construct the vascularized and neurotized tissue engineered bone. Biomed Res Int, 2014, 2014: 281872. doi: 10.1155/2014/281872.
2.	Fan JJ, Mu TW, Qin JJ, et al. Different effects of implanting sensory nerve or blood vessel on the vascularization, neurotization, and osteogenesis of tissue-engineered bone in vivo. Biomed Res Int, 2014, 2014: 412570. doi: 10.1155/2014/412570.
3.	Valtanen RS, Yang YP, Gurtner GC, et al. Synthetic and bone tissue engineering graft substitutes: What is the future? Injury, 2021, 52 Suppl 2: S72-S77.
4.	Brady RD, Grills BL, Church JE, et al. Closed head experimental traumatic brain injury increases size and bone volume of callus in mice with concomitant tibial fracture. Sci Rep, 2016, 6: 34491. doi: 10.1038/srep34491.
5.	Mollahosseini M, Ahmadirad H, Goujani R, et al. The association between traumatic brain injury and accelerated fracture healing: A study on the effects of growth factors and cytokines. J Mol Neurosci, 2021, 71(1): 162-168.
6.	Florencio-Silva R, Sasso GR, Sasso-Cerri E, et al. Biology of bone tissue: Structure, function, and factors that influence bone cells. Biomed Res Int, 2015, 2015: 421746. doi: 10.1155/2015/421746.
7.	Ascenzi MG. Theoretical mathematics, polarized light microscopy and computational models in healthy and pathological bone. Bone, 2020, 134: 115295. doi: 10.1016/j.bone.2020.115295.
8.	Huang S, Li Z, Liu Y, et al. Neural regulation of bone remodeling: Identifying novel neural molecules and pathways between brain and bone. J Cell Physiol, 2019, 234(5): 5466-5477.
9.	Wang X, Xu J, Kang Q. Neuromodulation of bone: Role of different peptides and their interactions (Review). Mol Med Rep, 2021, 23(1): 32. doi: 10.3892/mmr.2020.11670.
10.	王坤靓, 秦本刚. 周围神经错配再生的研究进展. 中国修复重建外科杂志, 2021, 35(3): 387-391.
11.	Monje PV. Schwann cell cultures: Biology, technology and therapeutics. Cells, 2020, 9(8): 1848. doi: 10.3390/cells9081848.
12.	Cai XX, Luo E, Yuan Q. Interaction between Schwann cells and osteoblasts in vitro. Int J Oral Sci, 2010, 2(2): 74-81.
13.	Itoyama T, Yoshida S, Tomokiyo A, et al. Possible function of GDNF and Schwann cells in wound healing of periodontal tissue. J Periodontal Res, 2020, 55(6): 830-839.
14.	Jones RE, Salhotra A, Robertson KS, et al. Skeletal stem cell-Schwann cell circuitry in mandibular repair. Cell Rep, 2019, 28(11): 2757-2766.
15.	Wu Z, Pu P, Su Z, et al. Schwann cell-derived exosomes promote bone regeneration and repair by enhancing the biological activity of porous Ti6Al4V scaffolds. Biochem Biophys Res Commun, 2020, 531(4): 559-565.
16.	Wang D, Lyu Y, Yang Y, et al. Schwann cell-derived EVs facilitate dental pulp regeneration through endogenous stem cell recruitment via SDF-1/CXCR4 axis. Acta Biomater, 2021. doi: 10.1016/j.actbio.2021.11.039.
17.	Johnston AP, Yuzwa SA, Carr MJ, et al. Dedifferentiated Schwann cell precursors secreting paracrine factors are required for regeneration of the mammalian digit tip. Cell Stem Cell, 2016, 19(4): 433-448.
18.	Parfejevs V, Debbache J, Shakhova O, et al. Injury-activated glial cells promote wound healing of the adult skin in mice. Nat Commun, 2018, 9(1): 236. doi: 10.1038/s41467-017-01488-2.
19.	Zhang X, Jiang X, Jiang S, et al. Schwann cells promote prevascularization and osteogenesis of tissue-engineered bone via bone marrow mesenchymal stem cell-derived endothelial cells. Stem Cell Res Ther, 2021, 12(1): 382. doi: 10.1186/s13287-021-02433-3.
20.	Ramos T, Ahmed M, Wieringa P, et al. Schwann cells promote endothelial cell migration. Cell Adh Migr, 2015, 9(6): 441-451.
21.	Wang Y, Zhang G, Hou Y, et al. Transplantation of microencapsulated Schwann cells and mesenchymal stem cells augment angiogenesis and improve heart function. Mol Cell Biochem, 2012, 366(1-2): 139-147.
22.	Kilian O, Hartmann S, Dongowski N, et al. BDNF and its TrkB receptor in human fracture healing. Ann Anat, 2014, 196(5): 286-295.
23.	Liu Q, Lei L, Yu T, et al. Effect of brain-derived neurotrophic factor on the neurogenesis and osteogenesis in bone engineering. Tissue Eng Part A, 2018, 24(15-16): 1283-1292.
24.	Zhang Z, Zhang Y, Zhou Z, et al. BDNF regulates the expression and secretion of VEGF from osteoblasts via the TrkB/ERK1/2 signaling pathway during fracture healing. Mol Med Rep, 2017, 15(3): 1362-1367.
25.	Su YW, Chung R, Ruan CS, et al. Neurotrophin-3 induces BMP-2 and VEGF activities and promotes the bony repair of injured growth plate cartilage and bone in rats. J Bone Miner Res, 2016, 31(6): 1258-1274.
26.	Zhang Z, Hu P, Wang Z, et al. BDNF promoted osteoblast migration and fracture healing by up-regulating integrin β1 via TrkB-mediated ERK1/2 and AKT signalling. J Cell Mol Med, 2020, 24(18): 10792-10802.
27.	Wang L, Zhou S, Liu B, et al. Locally applied nerve growth factor enhances bone consolidation in a rabbit model of mandibular distraction osteogenesis. J Orthop Res, 2006, 24(12): 2238-2245.
28.	Kajiya M, Shiba H, Fujita T, et al. Brain-derived neurotrophic factor stimulates bone/cementum-related protein gene expression in cementoblasts. J Biol Chem, 2008, 283(23): 16259-16267.
29.	Lee RH, Wong WL, Chan CH, et al. Differential effects of glial cell line-derived neurotrophic factor and neurturin in RET/GFRalpha1-expressing cells. J Neurosci Res, 2006, 83(1): 80-90.
30.	Sun CY, Chu ZB, She XM, et al. Brain-derived neurotrophic factor is a potential osteoclast stimulating factor in multiple myeloma. Int J Cancer, 2012, 130(4): 827-836.
31.	Ai LS, Sun CY, Zhang L, et al. Inhibition of BDNF in multiple myeloma blocks osteoclastogenesis via down-regulated stroma-derived RANKL expression both in vitro and in vivo. PLoS One, 2012, 7(10): e46287. doi: 10.1371/journal.pone.0046287.
32.	Shen L, Zeng W, Wu YX, et al. Neurotrophin-3 accelerates wound healing in diabetic mice by promoting a paracrine response in mesenchymal stem cells. Cell Transplant, 2013, 22(6): 1011-1021.
33.	Li X, Sun DC, Li Y, et al. Neurotrophin-3 improves fracture healing in rats. Eur Rev Med Pharmacol Sci, 2018, 22(8): 2439-2446.
34.	Su YW, Chim SM, Zhou L, et al. Osteoblast derived-neurotrophin-3 induces cartilage removal proteases and osteoclast-mediated function at injured growth plate in rats. Bone, 2018, 116: 232-247.
35.	Grills BL, Schuijers JA, Ward AR. Topical application of nerve growth factor improves fracture healing in rats. J Orthop Res, 1997, 15(2): 235-242.
36.	Rahbek UL, Dissing S, Thomassen C, et al. Nerve growth factor activates aorta endothelial cells causing PI3K/Akt- and ERK-dependent migration. Pflugers Arch, 2005, 450(5): 355-361.
37.	Hemingway F, Taylor R, Knowles HJ, et al. RANKL-independent human osteoclast formation with APRIL, BAFF, NGF, IGF Ⅰ and IGF Ⅱ. Bone, 2011, 48(4): 938-944.
38.	Yi S, Kim J, Lee SY. GDNF secreted by pre-osteoclasts induces migration of bone marrow mesenchymal stem cells and stimulates osteogenesis. BMB Rep, 2020, 53(12): 646-651.
39.	Wang H, Su K, Su L, et al. Comparison of 3D-printed porous tantalum and titanium scaffolds on osteointegration and osteogenesis. Mater Sci Eng C Mater Biol Appl, 2019, 104: 109908. doi: 10.1016/j.msec.2019.109908.
40.	Cipriano J, Lakshmikanthan A, Buckley C, et al. Characterization of a prevascularized biomimetic tissue engineered scaffold for bone regeneration. J Biomed Mater Res B Appl Biomater, 2020, 108(4): 1655-1668.
41.	Vidal L, Brennan MÁ, Krissian S, et al. In situ production of pre-vascularized synthetic bone grafts for regenerating critical-sized defects in rabbits. Acta Biomater, 2020, 114: 384-394.
42.	Yuan Q, Gong P, Tan Z. Schwann cell graft: a method to promote sensory responses of osseointegrated implants. Med Hypotheses, 2007, 69(4): 800-803.
43.	Hade MD, Suire CN, Suo Z. Mesenchymal stem cell-derived exosomes: Applications in regenerative medicine. Cells, 2021, 10(8): 1959. doi: 10.3390/cells10081959.

1. Fan J, Bi L, Jin D, et al. Microsurgical techniques used to construct the vascularized and neurotized tissue engineered bone. Biomed Res Int, 2014, 2014: 281872. doi: 10.1155/2014/281872.
2. Fan JJ, Mu TW, Qin JJ, et al. Different effects of implanting sensory nerve or blood vessel on the vascularization, neurotization, and osteogenesis of tissue-engineered bone in vivo. Biomed Res Int, 2014, 2014: 412570. doi: 10.1155/2014/412570.
3. Valtanen RS, Yang YP, Gurtner GC, et al. Synthetic and bone tissue engineering graft substitutes: What is the future? Injury, 2021, 52 Suppl 2: S72-S77.
4. Brady RD, Grills BL, Church JE, et al. Closed head experimental traumatic brain injury increases size and bone volume of callus in mice with concomitant tibial fracture. Sci Rep, 2016, 6: 34491. doi: 10.1038/srep34491.
5. Mollahosseini M, Ahmadirad H, Goujani R, et al. The association between traumatic brain injury and accelerated fracture healing: A study on the effects of growth factors and cytokines. J Mol Neurosci, 2021, 71(1): 162-168.
6. Florencio-Silva R, Sasso GR, Sasso-Cerri E, et al. Biology of bone tissue: Structure, function, and factors that influence bone cells. Biomed Res Int, 2015, 2015: 421746. doi: 10.1155/2015/421746.
7. Ascenzi MG. Theoretical mathematics, polarized light microscopy and computational models in healthy and pathological bone. Bone, 2020, 134: 115295. doi: 10.1016/j.bone.2020.115295.
8. Huang S, Li Z, Liu Y, et al. Neural regulation of bone remodeling: Identifying novel neural molecules and pathways between brain and bone. J Cell Physiol, 2019, 234(5): 5466-5477.
9. Wang X, Xu J, Kang Q. Neuromodulation of bone: Role of different peptides and their interactions (Review). Mol Med Rep, 2021, 23(1): 32. doi: 10.3892/mmr.2020.11670.
10. 王坤靓, 秦本刚. 周围神经错配再生的研究进展. 中国修复重建外科杂志, 2021, 35(3): 387-391.
11. Monje PV. Schwann cell cultures: Biology, technology and therapeutics. Cells, 2020, 9(8): 1848. doi: 10.3390/cells9081848.
12. Cai XX, Luo E, Yuan Q. Interaction between Schwann cells and osteoblasts in vitro. Int J Oral Sci, 2010, 2(2): 74-81.
13. Itoyama T, Yoshida S, Tomokiyo A, et al. Possible function of GDNF and Schwann cells in wound healing of periodontal tissue. J Periodontal Res, 2020, 55(6): 830-839.
14. Jones RE, Salhotra A, Robertson KS, et al. Skeletal stem cell-Schwann cell circuitry in mandibular repair. Cell Rep, 2019, 28(11): 2757-2766.
15. Wu Z, Pu P, Su Z, et al. Schwann cell-derived exosomes promote bone regeneration and repair by enhancing the biological activity of porous Ti6Al4V scaffolds. Biochem Biophys Res Commun, 2020, 531(4): 559-565.
16. Wang D, Lyu Y, Yang Y, et al. Schwann cell-derived EVs facilitate dental pulp regeneration through endogenous stem cell recruitment via SDF-1/CXCR4 axis. Acta Biomater, 2021. doi: 10.1016/j.actbio.2021.11.039.
17. Johnston AP, Yuzwa SA, Carr MJ, et al. Dedifferentiated Schwann cell precursors secreting paracrine factors are required for regeneration of the mammalian digit tip. Cell Stem Cell, 2016, 19(4): 433-448.
18. Parfejevs V, Debbache J, Shakhova O, et al. Injury-activated glial cells promote wound healing of the adult skin in mice. Nat Commun, 2018, 9(1): 236. doi: 10.1038/s41467-017-01488-2.
19. Zhang X, Jiang X, Jiang S, et al. Schwann cells promote prevascularization and osteogenesis of tissue-engineered bone via bone marrow mesenchymal stem cell-derived endothelial cells. Stem Cell Res Ther, 2021, 12(1): 382. doi: 10.1186/s13287-021-02433-3.
20. Ramos T, Ahmed M, Wieringa P, et al. Schwann cells promote endothelial cell migration. Cell Adh Migr, 2015, 9(6): 441-451.
21. Wang Y, Zhang G, Hou Y, et al. Transplantation of microencapsulated Schwann cells and mesenchymal stem cells augment angiogenesis and improve heart function. Mol Cell Biochem, 2012, 366(1-2): 139-147.
22. Kilian O, Hartmann S, Dongowski N, et al. BDNF and its TrkB receptor in human fracture healing. Ann Anat, 2014, 196(5): 286-295.
23. Liu Q, Lei L, Yu T, et al. Effect of brain-derived neurotrophic factor on the neurogenesis and osteogenesis in bone engineering. Tissue Eng Part A, 2018, 24(15-16): 1283-1292.
24. Zhang Z, Zhang Y, Zhou Z, et al. BDNF regulates the expression and secretion of VEGF from osteoblasts via the TrkB/ERK1/2 signaling pathway during fracture healing. Mol Med Rep, 2017, 15(3): 1362-1367.
25. Su YW, Chung R, Ruan CS, et al. Neurotrophin-3 induces BMP-2 and VEGF activities and promotes the bony repair of injured growth plate cartilage and bone in rats. J Bone Miner Res, 2016, 31(6): 1258-1274.
26. Zhang Z, Hu P, Wang Z, et al. BDNF promoted osteoblast migration and fracture healing by up-regulating integrin β1 via TrkB-mediated ERK1/2 and AKT signalling. J Cell Mol Med, 2020, 24(18): 10792-10802.
27. Wang L, Zhou S, Liu B, et al. Locally applied nerve growth factor enhances bone consolidation in a rabbit model of mandibular distraction osteogenesis. J Orthop Res, 2006, 24(12): 2238-2245.
28. Kajiya M, Shiba H, Fujita T, et al. Brain-derived neurotrophic factor stimulates bone/cementum-related protein gene expression in cementoblasts. J Biol Chem, 2008, 283(23): 16259-16267.
29. Lee RH, Wong WL, Chan CH, et al. Differential effects of glial cell line-derived neurotrophic factor and neurturin in RET/GFRalpha1-expressing cells. J Neurosci Res, 2006, 83(1): 80-90.
30. Sun CY, Chu ZB, She XM, et al. Brain-derived neurotrophic factor is a potential osteoclast stimulating factor in multiple myeloma. Int J Cancer, 2012, 130(4): 827-836.
31. Ai LS, Sun CY, Zhang L, et al. Inhibition of BDNF in multiple myeloma blocks osteoclastogenesis via down-regulated stroma-derived RANKL expression both in vitro and in vivo. PLoS One, 2012, 7(10): e46287. doi: 10.1371/journal.pone.0046287.
32. Shen L, Zeng W, Wu YX, et al. Neurotrophin-3 accelerates wound healing in diabetic mice by promoting a paracrine response in mesenchymal stem cells. Cell Transplant, 2013, 22(6): 1011-1021.
33. Li X, Sun DC, Li Y, et al. Neurotrophin-3 improves fracture healing in rats. Eur Rev Med Pharmacol Sci, 2018, 22(8): 2439-2446.
34. Su YW, Chim SM, Zhou L, et al. Osteoblast derived-neurotrophin-3 induces cartilage removal proteases and osteoclast-mediated function at injured growth plate in rats. Bone, 2018, 116: 232-247.
35. Grills BL, Schuijers JA, Ward AR. Topical application of nerve growth factor improves fracture healing in rats. J Orthop Res, 1997, 15(2): 235-242.
36. Rahbek UL, Dissing S, Thomassen C, et al. Nerve growth factor activates aorta endothelial cells causing PI3K/Akt- and ERK-dependent migration. Pflugers Arch, 2005, 450(5): 355-361.
37. Hemingway F, Taylor R, Knowles HJ, et al. RANKL-independent human osteoclast formation with APRIL, BAFF, NGF, IGF Ⅰ and IGF Ⅱ. Bone, 2011, 48(4): 938-944.
38. Yi S, Kim J, Lee SY. GDNF secreted by pre-osteoclasts induces migration of bone marrow mesenchymal stem cells and stimulates osteogenesis. BMB Rep, 2020, 53(12): 646-651.
39. Wang H, Su K, Su L, et al. Comparison of 3D-printed porous tantalum and titanium scaffolds on osteointegration and osteogenesis. Mater Sci Eng C Mater Biol Appl, 2019, 104: 109908. doi: 10.1016/j.msec.2019.109908.
40. Cipriano J, Lakshmikanthan A, Buckley C, et al. Characterization of a prevascularized biomimetic tissue engineered scaffold for bone regeneration. J Biomed Mater Res B Appl Biomater, 2020, 108(4): 1655-1668.
41. Vidal L, Brennan MÁ, Krissian S, et al. In situ production of pre-vascularized synthetic bone grafts for regenerating critical-sized defects in rabbits. Acta Biomater, 2020, 114: 384-394.
42. Yuan Q, Gong P, Tan Z. Schwann cell graft: a method to promote sensory responses of osseointegrated implants. Med Hypotheses, 2007, 69(4): 800-803.
43. Hade MD, Suire CN, Suo Z. Mesenchymal stem cell-derived exosomes: Applications in regenerative medicine. Cells, 2021, 10(8): 1959. doi: 10.3390/cells10081959.

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