Combination of biomaterial transplantation and genetic enhancement of intrinsic growth capacities to promote CNS axon regeneration after spinal cord injury

doi:10.1007/s11684-018-0642-z

Frontiers of Medicine

2019, Vol. 13

Issue (2): 131-137 https://doi.org/10.1007/s11684-018-0642-z

本期目录

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

全文: PDF(272 KB) HTML

Abstract：

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.

Key words： spinal cord injury biomaterial extrinsic barrier intrinsic regeneration capacity

收稿日期: 2017-11-20 出版日期: 2019-03-28

Corresponding Author(s): Xiaosong Gu

引用本文:

. [J]. Frontiers of Medicine, 2019, 13(2): 131-137.
Bin Yu, Xiaosong Gu. Combination of biomaterial transplantation and genetic enhancement of intrinsic growth capacities to promote CNS axon regeneration after spinal cord injury. Front. Med., 2019, 13(2): 131-137.

链接本文:

https://academic.hep.com.cn/fmd/CN/10.1007/s11684-018-0642-z
https://academic.hep.com.cn/fmd/CN/Y2019/V13/I2/131

Fig.1

1	ORaineteau, ME Schwab. Plasticity of motor systems after incomplete spinal cord injury. Nat Rev Neurosci 2001; 2(4): 263–273 https://doi.org/10.1038/35067570 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 https://doi.org/10.1038/nrn3680 pmid: 24840802
3	SDavid, A Kroner. Repertoire of microglial and macrophage responses after spinal cord injury. Nat Rev Neurosci 2011; 12(7): 388–399 https://doi.org/10.1038/nrn3053 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 https://doi.org/10.1016/S0306-4522(97)00011-0 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 https://doi.org/10.1093/jnen/61.7.623 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 https://doi.org/10.1093/brain/awl296 pmid: 17071951
7	MSBeattie. Inflammation and apoptosis: linked therapeutic targets in spinal cord injury. Trends Mol Med 2004; 10(12): 580–583 https://doi.org/10.1016/j.molmed.2004.10.006 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 https://doi.org/10.1097/01.WCB.0000061881.75234.5E 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 https://doi.org/10.1523/JNEUROSCI.0305-05.2005 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 https://doi.org/10.1016/S0014-4886(03)00257-7 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 https://doi.org/10.1016/j.annrmp.2008.10.004 pmid: 19886026
12	GYiu, Z He. Glial inhibition of CNS axon regeneration. Nat Rev Neurosci 2006; 7(8): 617–627 https://doi.org/10.1038/nrn1956 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 https://doi.org/10.1101/cshperspect.a020602 pmid: 25475091
14	MESchwab, SM Strittmatter. Nogo limits neural plasticity and recovery from injury. Curr Opin Neurobiol 2014; 27: 53–60 https://doi.org/10.1016/j.conb.2014.02.011 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 https://doi.org/10.1083/jcb.120.3.815 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 https://doi.org/10.1523/JNEUROSCI.19-19-08182.1999 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 https://doi.org/10.1016/S0014-4886(05)80013-5 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 https://doi.org/10.1006/exnr.1995.1081 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 https://doi.org/10.1016/j.neuroscience.2006.01.055 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 https://doi.org/10.1523/JNEUROSCI.23-01-00175.2003 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 https://doi.org/10.1038/nature17623 pmid: 27027288
22	ADGaudet, PG Popovich. Extracellular matrix regulation of inflammation in the healthy and injured spinal cord. Exp Neurol 2014; 258: 24–34 https://doi.org/10.1016/j.expneurol.2013.11.020 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 https://doi.org/10.1186/scrt480 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 https://doi.org/10.1002/jnr.490410407 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 https://doi.org/10.1016/j.biomaterials.2010.08.040 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 https://doi.org/10.1089/ten.tea.2011.0430 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 https://doi.org/10.1016/j.biomaterials.2014.11.031 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 https://doi.org/10.1523/JNEUROSCI.1996-14.2014 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 https://doi.org/10.1016/j.cell.2012.08.020 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 https://doi.org/10.1016/j.neuron.2014.07.014 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 https://doi.org/10.1038/nm.4066 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 https://doi.org/10.1016/j.biomaterials.2008.10.063 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 https://doi.org/10.1073/pnas.1510194112 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 https://doi.org/10.1073/pnas.1510176112 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 https://doi.org/10.1089/ten.2006.12.2777 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 https://doi.org/10.1016/j.biomaterials.2010.04.035 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 https://doi.org/10.1016/j.biomaterials.2012.10.070 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 https://doi.org/10.1523/JNEUROSCI.1864-09.2009 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 https://doi.org/10.1016/j.neuron.2010.05.002 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 https://doi.org/10.1126/science.1068428 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 https://doi.org/10.1523/JNEUROSCI.21-13-04731.2001 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 https://doi.org/DOI: 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 https://doi.org/10.1126/science.1175737 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 https://doi.org/10.1073/pnas.1120684109 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 https://doi.org/10.1016/j.neuron.2017.05.035 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 https://doi.org/10.1126/science.1161566 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 https://doi.org/10.1016/j.neuron.2015.03.060 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 https://doi.org/10.1038/nn.2603 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 https://doi.org/10.1038/nrm3330 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 https://doi.org/10.1038/nature10594 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 https://doi.org/10.1016/j.neuron.2015.02.017 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 https://doi.org/10.1016/j.neuron.2017.07.037 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 https://doi.org/10.1016/j.cell.2015.11.036 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 https://doi.org/10.1016/j.neuron.2014.07.014 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 https://doi.org/10.1038/nm.4066 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 https://doi.org/10.1038/nn.2377 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 https://doi.org/10.1038/nature13974 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 https://doi.org/10.1038/nn.4340 pmid: 27399843

Viewed

Full text

Abstract

Cited

Shared

Discussed