Overview and Description
While long-established scientific doctrine has held that central nervous system (CNS) axons have limited regenerative capacity following stroke, brain injury, cerebral palsy, degenerative brain diseases, or spinal cord injury, several advances in the understanding of natural recovery and regeneration of CNS tissue represent exciting developments for the fields of physiatry and neurorehabilitation. Ongoing research has been directed toward understanding axon regeneration, neuronal survival and myelination. Of particular interest, studies of the spinal cord and visual system offer insight into the function of various neural circuits providing valuable information on recovery and regeneration mechanisms.1,2 Understanding how nerve injury and repair are handled differently in the CNS and peripheral nervous system (PNS) allows for recognition of the various intrinsic factors involved in the repair and regeneration process.
The nervous system is made up of both the CNS and PNS, the later which has the ability to regenerate. During development, CNS neurons lose the ability to regenerate. There are inhibitory factors present and a lack of myelin clearance. This contributes to a toxic environment, preventing repair and regeneration.3 Neurogenesis, the process by which new nerve cells develop through differentiation from undifferentiated neural progenitor or stem cells, begins during prenatal development and continues in the hippocampus and subventricular area in the adult brain after most other CNS tissues have reached maturity. Neurogenesis is one of three mechanisms of plasticity in the brain, together with synaptic plasticity and functional compensatory processing.4 Briefly, synaptic plasticity facilitates neural transmission between nerves by enhancing synapses, and functional compensatory processing builds alternate circuits by recruiting inactive areas. The most significant advantage of neurogenesis, compared with other mechanisms of brain plasticity, is its ability to replace injured tissue with cells that mirror it in structural anatomy and function.
In the spinal cord, many research efforts have focused on neuroprotection rather than regeneration as a result of the perception that CNS axons in the spinal cord have little potential for repair following injury.5 However, more recently studies in animal models have shown that CNS axons in the mammalian spinal cord can regenerate provided they are given an environment that does not inhibit regrowth.6,7 It has been shown that neural progenitor cell grafts can assist corticospinal motor axons to reinnervate neurons distal to the lesion.This suggests that reinnervation of neurons is possible without typical guidance cueing.8 In addition, growing body of research has explored whether stem cell therapies, cell and/or tissue transplants, growth factors, biomaterials, genetic manipulations, or some combination of these approaches can result in axonal regeneration after spinal cord injury.9-18 After an injury, the immune system removes damaged axons. The process differs in the CNS and PNS. In the CNS, Microglia and Astrocytes are involved in clearing debris, while Schwann cells are involved in the PNS. Microglia induce cytokines such as TNF and IL-A, which are cytotoxic. Schwann cells not only clear debris, with the help of macrophages, but also differentiate into repair cells, speeding up the recovery process in PNS injury. Oligodendrocytes myelinate CNS axons. These cells do not help with the repair process. Debris clearing takes much longer in the CNS, about three months, where the PNS it takes about a month. In spinal cord injury, microglia depletion has led to disorganized astrocyte scarring and impaired recovery, since there is a reduction of the number of neurons present. This suggests microglia are important for the protective scar that forms, can be studied further for regenerative purposes.19
Successful neurogenesis requires that undifferentiated neural progenitor or stem cells survive and terminally differentiate according to appropriate structural and functional anatomical correlates. To date, most stem cell research focused on CNS regeneration has focused on multipotent mesenchymal stromal cell (MSC) and neural stem cell (NSC) therapies. MSCs may be obtained from bone marrow, cord blood, placenta, and adipose tissues and are hypothesized to provide a supportive environment by promoting endogenous neurogenesis and angiogenesis following CNS injury by way of reducing inflammation and exerting immunomodulatory and hormonal effects.20 By comparison, NSCs may be obtained via direct extraction from primary CNS tissues, including fetal brain, adult brain, and spinal cord tissue, differentiation from pluripotent stem cells, such as embryonic stem cells and induced pluripotent stem cells, and trans-differentiation from somatic cells.21
Retinal ganglion cells, (RGC’s) which are considered CNS neurons, are being studied for their regenerative properties. With injury, some of these neurons die quickly, while others survive for about 8 days. RGC’s are the target of drug treatments and continuously being studied. In mammals, certain growth factors are present in higher concentration in RGC’s suggesting their resilience to neuronal death. In addition, there are other genes and transcription factors present in RGC’s, which offer neuroprotection and are currently being studied.19 Numerous studies have also investigated the role of physical activity in facilitating neurogenesis in neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and age-related cognitive decline in the absence of acute CNS injury.22-24
Relevance to Clinical Practice
While many exciting research developments are underway that may unlock the potential to stimulate neurogenesis following CNS injury and lead to greater functional recovery,25 clinicians are often faced with an absence of commercially available treatments for use in everyday practice beyond standard rehabilitation approaches, compensatory strategies, and mainstays of general health maintenance such as regular physical activity and preventive care. Even though animal studies have yielded successes at curing some CNS disorders, there has not been a successful transition to cure the same CNS disorders in humans.26 Nonetheless, individuals with CNS injury and neurodegenerative disease may inquire about experimental clinical trials for novel therapies and/or interventions aimed at neural regeneration.
Currently, there are ongoing research trials at the mayo clinic for Alzheimer’s disease, Amyotrophic lateral sclerosis, Parkinson’s disease, and Multiple sclerosis among others. There are trials investigating stem cell use, gene therapy and growth factor driven restoration of tissues in the CNS. The use of growth factors for example to promote axon regeneration of the spinal cord in rats and mice is being studied for human application. Zebrafish are being used to understand how nerve cells are developed and how regeneration after injury occurs. Mesenchymal stem cells have the ability to differentiate into various tissues such as bone, muscle and cartilage. Study of these cells in animal models with hemorrhagic stroke have yielded results of improved limb function. Kallikreins, which regulate proteolytic cascades as a result of CNS trauma, are being targeted to avert the inflammatory cascade and prevent tissue injury. The use of Deep brain stimulation (DBS) to the fornix and hypothalamus is reported to have an improvement in memory and decrease cognitive decline in patient with early Alzheimer’s. Researchers are investigating use of DBS which could be a potential treatment if studies yield promising results.27
Clinicians who wish to establish trusted communication around experimental clinical trials with patients and/or families should maintain an open and transparent attitude about discussing novel treatments, be willing to engage with patients and/or families about experimental clinical trials, maintain working knowledge of current clinical trial resources and legitimate sources of information, and respect for patients’ autonomy and choices in a given clinical relationship.28
Cutting Edge/ Unique Concepts/ Emerging Issues
Novel treatments to promote neurogenesis following CNS injury are currently available to eligible participants of clinical experimental research trials. Research has yet to establish the optimal delivery route, method of delivery, dosage, and timing of cell-based treatments and those involving novel biomaterials, pharmaceutical compounds, and/or growth factors. Toxicities and unintended effects of new treatment approaches, especially potential long-term side effects, have yet to be established conclusively.29 Tumorigenesis as a potential long-term complication remains an important concern for trials of undifferentiated neural progenitor or stem cells based upon animal models and case reports in humans.30-32 The upregulation of pro-growth factors can lead to tumorigenesis, thus many studies are shifting their focus to axon repair and regeneration as opposed to the use of growth factors.33
Gaps in Knowledge/ Evidence Base
Most clinical human studies of stem cell therapy for neurogenesis following CNS injury are currently aimed at establishing safety and efficacy based on dosing parameters. Large scale, population-based studies of novel therapeutic techniques are lacking and difficult to perform due to patient selection restrictions in preliminary investigations. Clinicians may face practical challenges when discussing novel treatments with individuals who have sustained a CNS injury and may have received information on unproven therapies available commercially that are marketed as direct-to-consumer treatments and have not been thoroughly tested or lack safety oversight and monitoring if they are not part of a clinical research trial.34 Clinicians and researchers working with individuals who have sustained CNS injuries must maintain an awareness of industry standards of informed consent for novel therapeutic treatments, potential ethical issues regarding participation in experimental clinical trials, and consumer-facing resources and educational materials.35-37
- Bray ER, Yungher BJ, Levay K, Ribeiro M, Dvoryanchikov G, Ayupe AC, Thakor K, Marks V, Randolph M, Danzi MC, Schmidt TM, Chaudhari N, Lemmon VP, Hattar S, Park KK. Thrombospondin-1 Mediates Axon Regeneration in Retinal Ganglion Cells. Neuron. 2019 Aug 21;103(4):642-657.e7. doi: 10.1016/j.neuron.2019.05.044. Epub 2019 Jun 26. PMID: 31255486; PMCID: PMC6706310.
- Uyeda A, Muramatsu R. Molecular Mechanisms of Central Nervous System Axonal Regeneration and Remyelination: A Review. Int J Mol Sci. 2020 Oct 30;21(21):8116. doi: 10.3390/ijms21218116. PMID: 33143194; PMCID: PMC7662268.
- Nagappan, P. G., Chen, H., & Wang, D.-Y. (2020). Neuroregeneration and plasticity: A review of the physiological mechanisms for achieving functional recovery postinjury. Military Medical Research, 7(1).
- Sophie Su YR, Veeravagu A, Grant G. Neuroplasticity after Traumatic Brain Injury. In: Laskowitz D, Grant G, editors. Translational Research in Traumatic Brain Injury. Boca Raton (FL): CRC Press/Taylor and Francis Group; 2016. Chapter 8.
- Tsai E, Chen S, Turner A. Why Don’t We Have a Cure for Spinal Cord Injury? AANS Neurosurgeon. 2016:25(3).
- Richardson PM, Issa VM, Aguayo AJ. Regeneration of long spinal axons in the rat. Journal of neurocytology. 1984 Feb 1;13(1):165-82.
- Kempermann G, Gage FH, Aigner L, et al. Human Adult Neurogenesis: Evidence and Remaining Questions. Cell Stem Cell. 2018;23(1):25-30.
- Ceto, S., Sekiguchi, K. J., Takashima, Y., Nimmerjahn, A., & Tuszynski, M. H. (2020). Neural stem cell grafts form extensive synaptic networks that integrate with host circuits after Spinal Cord Injury. Cell Stem Cell, 27(3).
- Liu J, Chen P, Wang Q, Chen Y, Yu H, Ma J, Guo M, Piao M, Ren W, Xiang L. Meta analysis of olfactory ensheathing cell transplantation promoting functional recovery of motor nerves in rats with complete spinal cord transection. Neural regeneration research. 2014 Oct 15;9(20):1850.
- Harvey AR, Lovett SJ, Majda BT, Yoon JH, Wheeler LP, Hodgetts SI. Neurotrophic factors for spinal cord repair: which, where, how and when to apply, and for what period of time?. Brain research. 2015 Sep 4;1619:36-71.
- Raspa A, Pugliese R, Maleki M, Gelain F. Recent therapeutic approaches for spinal cord injury. Biotechnology and bioengineering. 2016 Feb;113(2):253-9.
- Assunção-Silva RC, Gomes ED, Sousa N, Silva NA, Salgado AJ. Hydrogels and cell based therapies in spinal cord injury regeneration. Stem cells international. 2015;2015.
- Tsai EC, Dalton PD, Shoichet MS, Tator CH. Synthetic hydrogel guidance channels facilitate regeneration of adult rat brainstem motor axons after complete spinal cord transection. Journal of neurotrauma. 2004 Jun 1;21(6):789-804.
- Tsai EC, Dalton PD, Shoichet MS, Tator CH. Matrix inclusion within synthetic hydrogel guidance channels improves specific supraspinal and local axonal regeneration after complete spinal cord transection. Biomaterials. 2006 Jan 1;27(3):519-33.
- Fagoe ND, van Heest J, Verhaagen J. Spinal cord injury and the neuron-intrinsic regeneration-associated gene program. Neuromolecular medicine. 2014 Dec 1;16(4):799-813.
- Quiroz JF, Tsai E, Coyle M, Sehm T, Echeverri K. Precise control of miR-125b levels is required to create a regeneration-permissive environment after spinal cord injury: a cross-species comparison between salamander and rat. Disease models & mechanisms. 2014 Jun 1;7(6):601-11.
- Young W. Spinal cord regeneration. Cell transplantation. 2014 May;23(4-5):573-611.
- Bellver-Landete, V., Bretheau, F., Mailhot, B., Vallières, N., Lessard, M., Janelle, M.-E., Vernoux, N., Tremblay, M.-È., Fuehrmann, T., Shoichet, M. S., & Lacroix, S. (2019). Microglia are an essential component of the neuroprotective scar that forms after spinal cord injury. Nature Communications, 10(1)
- Zhang Y, Chopp M, Meng Y, et al. Effect of exosomes derived from multipluripotent mesenchymal stromal cells on functional recovery and neurovascular plasticity in rats after traumatic brain injury. J Neurosurg. 2015;122(4):856-67.
- Tang Y, Yu P, Cheng L. Current progress in the derivation and therapeutic application of neural stem cells. Cell Death Dis. 2017;8(10):e3108.
- Tran, N. M., Shekhar, K., Whitney, I. E., Jacobi, A., Benhar, I., Hong, G., Yan, W., Adiconis, X., Arnold, M. K. E., Lee, J. M., Levin, J. Z., Lin, D., Wang, C., Lieber, C. M., Regev, A., He, Z., & Sanes, J. R. (2019). Single-cell profiles of retinal ganglion cells differing in resilience to injury reveal neuroprotective genes. Neuron, 104(6).
- Mak MK, Wong-yu IS, Shen X, Chung CL. Long-term effects of exercise and physical therapy in people with Parkinson disease. Nat Rev Neurol. 2017;13(11):689-703.
- Wang R, Holsinger RMD. Exercise-induced brain-derived neurotrophic factor expression: Therapeutic implications for Alzheimer’s dementia. Ageing Res Rev. 2018;48:109-121.
- Tortosa-martínez J, Manchado C, Cortell-tormo JM, Chulvi-medrano I. Exercise, the diurnal cycle of cortisol and cognitive impairment in older adults. Neurobiol Stress. 2018;9:40-47.
- Tetzlaff W, Okon EB, Karimi-abdolrezaee S, et al. A systematic review of cellular transplantation therapies for spinal cord injury. J Neurotrauma. 2011;28(8):1611-82.
- Makris, N., Tsintou, M., & Dalamagkas, K. (2020). Taking central nervous system regenerative therapies to the clinic: Curing rodents versus nonhuman primates versus humans. Neural Regeneration Research, 15(3), 425.
- Center for Regenerative Biotherapeutics – Neuroregeneration. (2017, February 2). Mayo Clinic. https://www.mayo.edu/research/centers-programs/center-regenerative-biotherapeutics/focus-areas/neuroregeneration
- Jacob KJ, Kwon BK, Lo C, Snyder J, Illes J. Perspectives on strategies and challenges in the conversation about stem cells for spinal cord injury. Spinal Cord. 2015;53(11):811-5.
- Fan X, Wang JZ, Lin XM, Zhang L. Stem cell transplantation for spinal cord injury: a meta-analysis of treatment effectiveness and safety. Neural Regen Res. 2017;12(5):815-825.
- Kojima K, Miyoshi H, Nagoshi N, et al. Selective Ablation of Tumorigenic Cells Following Human Induced Pluripotent Stem Cell-Derived Neural Stem/Progenitor Cell Transplantation in Spinal Cord Injury. Stem Cells Transl Med. 2019;8(3):260-270.
- Woodworth CF, Jenkins G, Barron J, Hache N. Intramedullary cervical spinal mass after stem cell transplantation using an olfactory mucosal cell autograft. CMAJ. 2019;191(27):E761-E764.
- Lima C, Escada P, Pratas-vital J, et al. Olfactory mucosal autografts and rehabilitation for chronic traumatic spinal cord injury. Neurorehabil Neural Repair. 2010;24(1):10-22.
- Varadarajan SG, Hunyara JL, Hamilton NR, Kolodkin AL, Huberman AD. Central nervous system regeneration. Cell. 2022 Jan 6;185(1):77-94.
- Sugarman J, Barker RA, Charo RA. A Professional Standard for Informed Consent for Stem Cell Therapies. JAMA. 2019.
- Lammertse DP. The Spinal Cord Outcomes Partnership Endeavor (SCOPE) SCI Clinical Trials Tables. Top Spinal Cord Inj Rehabil. 2016;22(4):288-315.
- ClinicalTrials.gov. U.S. National Library of Medicine. Bethesda, MD. Accessed 27 August 2019. https://clinicaltrials.gov
- Steeves J, Fawcett J, Tuszynski M, Lammertse D, Curt A, Fehlings M, et al. Experimental Treatments for Spinal Cord Injuries: What you should know if you are considering participation in a clinical trial. ICORD. Vancouver, BC. 2012. Accessed 27 August 2019. https://icord.org/wp-content/uploads/2014/01/Clinical-Trials-Document-V2-BL-Final.pdf
Original Version of the Topic
Chong Tae Kim, MD. Natural Recovery and Regeneration of the Central Nervous System. 11/05/2012
Previous Revision(s) of the Topic
Chloe Slocum, MD, MPH. Natural Recovery and Regeneration of the Central Nervous System. 10/29/2019
Hillary Ramroop, DO
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Rosanna C. Sabini, DO
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