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Frontiers of Medicine

Front. Med.    2019, Vol. 13 Issue (2) : 131-137
Combination of biomaterial transplantation and genetic enhancement of intrinsic growth capacities to promote CNS axon regeneration after spinal cord injury
Bin Yu, Xiaosong Gu()
Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China
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The inhibitory environment that surrounds the lesion site and the lack of intrinsic regenerative capacity of the adult mammalian central nervous system (CNS) impede the regrowth of injured axons and thereby the reestablishment of neural circuits required for functional recovery after spinal cord injuries (SCI). To circumvent these barriers, biomaterial scaffolds are applied to bridge the lesion gaps for the regrowing axons to follow, and, often by combining stem cell transplantation, to enable the local environment in the growth-supportive direction. Manipulations, such as the modulation of PTEN/mTOR pathways, can also enhance intrinsic CNS axon regrowth after injury. Given the complex pathophysiology of SCI, combining biomaterial scaffolds and genetic manipulation may provide synergistic effects and promote maximal axonal regrowth. Future directions will primarily focus on the translatability of these approaches and promote therapeutic avenues toward the functional rehabilitation of patients with SCIs.

Keywords spinal cord injury      biomaterial      extrinsic barrier      intrinsic regeneration capacity     
Corresponding Author(s): Xiaosong Gu   
Just Accepted Date: 25 July 2018   Online First Date: 31 August 2018    Issue Date: 28 March 2019
 Cite this article:   
Bin Yu,Xiaosong Gu. Combination of biomaterial transplantation and genetic enhancement of intrinsic growth capacities to promote CNS axon regeneration after spinal cord injury[J]. Front. Med., 2019, 13(2): 131-137.
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Bin Yu
Xiaosong Gu
Fig.1  Combinational strategies to enhance axon regrowth and functional recovery after SCI. CNS neurons switch from robust growth state to relatively static state during development, marked by expressional changes of key molecules and signaling pathways. After CNS injury, extrinsically, myelin-associated inhibitors (Nogo-A, MAG, OMgp), CSPGs, and glia scar/cavity create a high-growth impermissive environment. Successful axon regeneration is therefore impeded by intrinsic and extrinsic factors. By employing a biomaterial matrix that bridges the lesion site, providing growth-permissive environment by stem cells, or engineering the cell transplantation, the enhancement of axon regeneration induced by manipulation of cell autonomous growth capacity can synergistically boost and achieve significant functional recovery.
1 ORaineteau, ME Schwab. Plasticity of motor systems after incomplete spinal cord injury. Nat Rev Neurosci 2001; 2(4): 263–273 pmid: 11283749
2 LConforti, J Gilley, MPColeman. Wallerian degeneration: an emerging axon death pathway linking injury and disease. Nat Rev Neurosci 2014; 15(6): 394–409 pmid: 24840802
3 SDavid, A Kroner. Repertoire of microglial and macrophage responses after spinal cord injury. Nat Rev Neurosci 2011; 12(7): 388–399 pmid: 21673720
4 YTaoka, K Okajima, MUchiba, KMurakami, SKushimoto, MJohno, MNaruo, HOkabe, KTakatsuki. Role of neutrophils in spinal cord injury in the rat. Neuroscience 1997; 79(4): 1177–1182 pmid: 9219976
5 PGPopovich, Z Guan, VMcGaughy, LFisher, WFHickey, DMBasso. The neuropathological and behavioral consequences of intraspinal microglial/macrophage activation. J Neuropathol Exp Neurol 2002; 61(7): 623–633 pmid: 12125741
6 JCFleming, MD Norenberg, DARamsay, GADekaban, AEMarcillo, ADSaenz, MPasquale-Styles, WDDietrich, LCWeaver. The cellular inflammatory response in human spinal cords after injury. Brain 2006; 129(Pt 12): 3249–3269 pmid: 17071951
7 MSBeattie. Inflammation and apoptosis: linked therapeutic targets in spinal cord injury. Trends Mol Med 2004; 10(12): 580–583 pmid: 15567326
8 MSchwartz. Macrophages and microglia in central nervous system injury: are they helpful or harmful? J Cereb Blood Flow Metab 2003; 23(4): 385–394 pmid: 12679714
9 TBJones, RP Hart, PGPopovich. Molecular control of physiological and pathological T-cell recruitment after mouse spinal cord injury. J Neurosci 2005; 25(28): 6576–6583 pmid: 16014718
10 RGonzalez, J Glaser, MTLiu, TELane, HSKeirstead. Reducing inflammation decreases secondary degeneration and functional deficit after spinal cord injury. Exp Neurol 2003; 184(1): 456–463 pmid: 14637115
11 LBauchet, N Lonjon, FEPerrin, CGilbert, APrivat, CFattal. Strategies for spinal cord repair after injury: a review of the literature and information. Ann Phys Rehabil Med 2009; 52(4): 330–351 pmid: 19886026
12 GYiu, Z He. Glial inhibition of CNS axon regeneration. Nat Rev Neurosci 2006; 7(8): 617–627 pmid: 16858390
13 JSilver, ME Schwab, PGPopovich. Central nervous system regenerative failure: role of oligodendrocytes, astrocytes, and microglia. Cold Spring Harb Perspect Biol 2015; 7(3): a020602 pmid: 25475091
14 MESchwab, SM Strittmatter. Nogo limits neural plasticity and recovery from injury. Curr Opin Neurobiol 2014; 27: 53–60 pmid: 24632308
15 MGrumet, A Flaccus, RUMargolis. Functional characterization of chondroitin sulfate proteoglycans of brain: interactions with neurons and neural cell adhesion molecules. J Cell Biol 1993; 120(3): 815–824 pmid: 8425902
16 MTFitch, C Doller, CKCombs, GELandreth, JSilver. Cellular and molecular mechanisms of glial scarring and progressive cavitation: in vivo and in vitro analysis of inflammation-induced secondary injury after CNS trauma. J Neurosci 1999; 19(19): 8182–8198 pmid: 10493720
17 DMSnow, V Lemmon, DACarrino, AICaplan, JSilver. Sulfated proteoglycans in astroglial barriers inhibit neurite outgrowth in vitro. Exp Neurol 1990; 109(1): 111–130 pmid: 2141574
18 RJMcKeon, A Höke, JSilver. Injury-induced proteoglycans inhibit the potential for laminin-mediated axon growth on astrocytic scars. Exp Neurol 1995; 136(1): 32–43 pmid: 7589332
19 KERhodes, G Raivich, JWFawcett. The injury response of oligodendrocyte precursor cells is induced by platelets, macrophages and inflammation-associated cytokines. Neuroscience 2006; 140(1): 87–100 pmid: 16631314
20 YMUghrin, ZJ Chen, JMLevine. Multiple regions of the NG2 proteoglycan inhibit neurite growth and induce growth cone collapse. J Neurosci 2003; 23(1): 175–186 pmid: 12514214
21 MAAnderson, JE Burda, YRen, YAo, TM O’Shea, RKawaguchi, GCoppola, BSKhakh, TJDeming, MVSofroniew. Astrocyte scar formation aids central nervous system axon regeneration. Nature 2016; 532(7598): 195–200 pmid: 27027288
22 ADGaudet, PG Popovich. Extracellular matrix regulation of inflammation in the healthy and injured spinal cord. Exp Neurol 2014; 258: 24–34 pmid: 25017885
23 BShrestha, K Coykendall, YLi, AMoon, P Priyadarshani, LYao. Repair of injured spinal cord using biomaterial scaffolds and stem cells. Stem Cell Res Ther 2014; 5(4): 91 pmid: 25157690
24 EAJJoosten, PR Bär, WHGispen. Collagen implants and cortico-spinal axonal growth after mid-thoracic spinal cord lesion in the adult rat. J Neurosci Res 1995; 41(4): 481–490 pmid: 7473879
25 QHan, W Jin, ZXiao, HNi, J Wang, JKong, JWu, W Liang, LChen, YZhao, B Chen, JDai. The promotion of neural regeneration in an extreme rat spinal cord injury model using a collagen scaffold containing a collagen binding neuroprotective protein and an EGFR neutralizing antibody. Biomaterials 2010; 31(35): 9212–9220 pmid: 20869112
26 TLiu, JD Houle, JXu, BPChan, SYChew. Nanofibrous collagen nerve conduits for spinal cord repair. Tissue Eng Part A 2012; 18(9-10): 1057–1066 pmid: 22220714
27 SHan, B Wang, WJin, ZXiao, X Li, WDing, MKapur, BChen, B Yuan, TZhu, HWang, J Wang, QDong, WLiang, JDai. The linear-ordered collagen scaffold-BDNF complex significantly promotes functional recovery after completely transected spinal cord injury in canine. Biomaterials 2015; 41: 89–96 pmid: 25522968
28 MHSpilker, IV Yannas, SKKostyk, TVNorregaard, HPHsu, M Spector. The effects of tubulation on healing and scar formation after transection of the adult rat spinal cord. Restor Neurol Neurosci 2001; 18(1): 23–38
pmid: 11673667
29 GLewandowski, O Steward. AAV shRNA-mediated suppression of PTEN in adult rats in combination with salmon fibrin administration enables regenerative growth of corticospinal axons and enhances recovery of voluntary motor function after cervical spinal cord injury. J Neurosci 2014; 34(30): 9951–9962 pmid: 25057197
30 PLu, Y Wang, LGraham, KMcHale, MGao, D Wu, JBrock, ABlesch, ESRosenzweig, LAHavton, BZheng, JMConner, MMarsala, MHTuszynski. Long-distance growth and connectivity of neural stem cells after severe spinal cord injury. Cell 2012; 150(6): 1264–1273 pmid: 22980985
31 PLu, G Woodruff, YWang, LGraham, MHunt, D Wu, EBoehle, RAhmad, GPoplawski, JBrock, LSGoldstein, MHTuszynski. Long-distance axonal growth from human induced pluripotent stem cells after spinal cord injury. Neuron 2014; 83(4): 789–796 pmid: 25123310
32 KKadoya, P Lu, KNguyen, CLee-Kubli, HKumamaru, LYao, J Knackert, GPoplawski, JNDulin, HStrobl, YTakashima, JBiane, JConner, SCZhang, MHTuszynski. Spinal cord reconstitution with homologous neural grafts enables robust corticospinal regeneration. Nat Med 2016; 22(5): 479–487 pmid: 27019328
33 XLi, Z Yang, AZhang, TWang, W Chen. Repair of thoracic spinal cord injury by chitosan tube implantation in adult rats. Biomaterials 2009; 30(6): 1121–1132 pmid: 19042014
34 ZYang, A Zhang, HDuan, SZhang, PHao, K Ye, YESun, XLi. NT3-chitosan elicits robust endogenous neurogenesis to enable functional recovery after spinal cord injury. Proc Natl Acad Sci U S A 2015; 112(43): 13354–13359 pmid: 26460015
35 HDuan, W Ge, AZhang, YXi, Z Chen, DLuo, YCheng, KSFan, S Horvath, MVSofroniew, LCheng, ZYang, YE Sun, XLi. Transcriptome analyses reveal molecular mechanisms underlying functional recovery after spinal cord injury. Proc Natl Acad Sci U S A 2015; 112(43): 13360–13365 pmid: 26460053
36 SStokols, J Sakamoto, CBreckon, THolt, J Weiss, MHTuszynski. Templated agarose scaffolds support linear axonal regeneration. Tissue Eng 2006; 12(10): 2777–2787 pmid: 17518647
37 TGros, JS Sakamoto, ABlesch, LAHavton, MHTuszynski. Regeneration of long-tract axons through sites of spinal cord injury using templated agarose scaffolds. Biomaterials 2010; 31(26): 6719–6729 pmid: 20619785
38 MGao, P Lu, BBednark, DLynam, JMConner, JSakamoto, MHTuszynski. Templated agarose scaffolds for the support of motor axon regeneration into sites of complete spinal cord transection. Biomaterials 2013; 34(5): 1529–1536 pmid: 23182350
39 JKLee, AF Chan, SMLuu, YZhu, C Ho, MTessier-Lavigne, BZheng. Reassessment of corticospinal tract regeneration in Nogo-deficient mice. J Neurosci 2009; 29(27): 8649–8654 pmid: 19587271
40 JKLee, CG Geoffroy, AFChan, KETolentino, MJCrawford, MALeal, BKang, B Zheng. Assessing spinal axon regeneration and sprouting in Nogo-, MAG-, and OMgp-deficient mice. Neuron 2010; 66(5): 663–670 pmid: 20547125
41 JLGoldberg, MP Klassen, YHua, BABarres. Amacrine-signaled loss of intrinsic axon growth ability by retinal ganglion cells. Science 2002; 296(5574): 1860–1864 pmid: 12052959
42 DCai, J Qiu, ZCao, MMcAtee, BSBregman, MTFilbin. Neuronal cyclic AMP controls the developmental loss in ability of axons to regenerate. J Neurosci 2001; 21(13): 4731–4739 pmid: 11425900
43 YHao, E Frey, CYoon, HWong, D Nestorovski, LBHolzman, RJGiger, ADiAntonio, CCollins. An evolutionarily conserved mechanism for cAMP elicited axonal regeneration involves direct activation of the dual leucine zipper kinase DLK. eLife 2016; 5: e14048 10.7554/eLife.14048 pmid: 27268300
44 DLMoore, MG Blackmore, YHu, KHKaestner, JLBixby, VPLemmon, JLGoldberg. KLF family members regulate intrinsic axon regeneration ability. Science 2009; 326(5950): 298–301 pmid: 19815778
45 MGBlackmore, Z Wang, JKLerch, DMotti, YPZhang, CBShields, JKLee, JL Goldberg, VPLemmon, JLBixby. Krüppel-like Factor 7 engineered for transcriptional activation promotes axon regeneration in the adult corticospinal tract. Proc Natl Acad Sci U S A 2012; 109(19): 7517–7522 pmid: 22529377
46 MWNorsworthy, F Bei, RKawaguchi, QWang, NM Tran, YLi, BBrommer, YZhang, CWang, JR Sanes, GCoppola, ZHe. Sox11 expression promotes regeneration of some retinal ganglion cell types but kills others. Neuron 2017; 94(6): 1112–1120.e4 pmid: 28641110
47 KKPark, K Liu, YHu, PDSmith, CWang, B Cai, BXu, LConnolly, IKramvis, MSahin, ZHe. Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway. Science 2008; 322(5903): 963–966 pmid: 18988856
48 SBelin, H Nawabi, CWang, STang, A Latremoliere, PWarren, HSchorle, CUncu, CJ Woolf, ZHe, JASteen. Injury-induced decline of intrinsic regenerative ability revealed by quantitative proteomics. Neuron 2015; 86(4): 1000–1014 pmid: 25937169
49 KLiu, Y Lu, JKLee, RSamara, RWillenberg, ISears-Kraxberger, ATedeschi, KKPark, DJin, B Cai, BXu, LConnolly, OSteward, BZheng, ZHe. PTEN deletion enhances the regenerative ability of adult corticospinal neurons. Nat Neurosci 2010; 13(9): 1075–1081 pmid: 20694004
50 MSSong, L Salmena, PPPandolfi. The functions and regulation of the PTEN tumour suppressor. Nat Rev Mol Cell Biol 2012; 13(5): 283–296 pmid: 22473468
51 FSun, KK Park, SBelin, DWang, T Lu, GChen, KZhang, CYeung, GFeng, BA Yankner, ZHe. Sustained axon regeneration induced by co-deletion of PTEN and SOCS3. Nature 2011; 480(7377): 372–375 pmid: 22056987
52 XDuan, M Qiao, FBei, IJKim, Z He, JRSanes. Subtype-specific regeneration of retinal ganglion cells following axotomy: effects of osteopontin and mTOR signaling. Neuron 2015; 85(6): 1244–1256 pmid: 25754821
53 YLiu, X Wang, WLi, QZhang, YLi, Z Zhang, JZhu, BChen, PR Williams, YZhang, BYu, X Gu, ZHe. A sensitized IGF1 treatment restores corticospinal axon-dependent functions. Neuron 2017; 95(4): 817–833.e4 pmid: 28817801
54 FBei, HHC Lee, XLiu, GGunner, HJin, L Ma, CWang, LHou, TK Hensch, EFrank, JRSanes, CChen, M Fagiolini, ZHe. Restoration of visual function by enhancing conduction in regenerated axons. Cell 2016; 164(1-2): 219–232 pmid: 26771493
55 PLu, G Woodruff, YWang, LGraham, MHunt, D Wu, EBoehle, RAhmad, GPoplawski, JBrock, LSBGoldstein, MHTuszynski. Long-distance axonal growth from human induced pluripotent stem cells after spinal cord injury. Neuron 2014; 83(4): 789–796 pmid: 25123310
56 KKadoya, P Lu, KNguyen, CLee-Kubli, HKumamaru, LYao, J Knackert, GPoplawski, JNDulin, HStrobl, YTakashima, JBiane, JConner, SCZhang, MHTuszynski. Spinal cord reconstitution with homologous neural grafts enables robust corticospinal regeneration. Nat Med 2016; 22(5): 479–487 pmid: 27019328
57 GGarcía-Alías, SBarkhuysen, MBuckle, JWFawcett. Chondroitinase ABC treatment opens a window of opportunity for task-specific rehabilitation. Nat Neurosci 2009; 12(9): 1145–1151 pmid: 19668200
58 BTLang, JM Cregg, MADePaul, APTran, KXu, SM Dyck, KMMadalena, BPBrown, YLWeng, SLi, S Karimi-Abdolrezaee, SABusch, YShen, J Silver. Modulation of the proteoglycan receptor PTPs promotes recovery after spinal cord injury. Nature 2015; 518(7539): 404–408 pmid: 25470046
59 JHLim, BK Stafford, PLNguyen, BVLien, CWang, K Zukor, ZHe, ADHuberman. Neural activity promotes long-distance, target-specific regeneration of adult retinal axons. Nat Neurosci 2016; 19(8): 1073–1084 pmid: 27399843
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