Resumen
Introducción: los déficits motores, sensoriales y autonómicos devastadores, con escasa recuperación espontánea, son el resultado de la lesión de la médula espinal (LME). En el pasado, las estrategias terapéuticas se han centrado con frecuencia en la curación biológica o en la restauración funcional mediante rehabilitación. Los datos más recientes respaldan la rehabilitación regenerativa, la cual es una estrategia sinérgica que combina la medicina regenerativa y la rehabilitación basada en la actividad, para mejorar los resultados tras la LME.
Objetivo: el propósito de esta revisión es resumir las investigaciones más recientes sobre las técnicas de rehabilitación regenerativa para la LME, examinando sus mecanismos, los avances en la traslación y sus posibles aplicaciones en entornos clínicos.
Métodos: se realizó una búsqueda bibliográfica exhaustiva sobre lesión de médula espinal, medicina regenerativa, neurorrehabilitación, células madre y neuroplasticidad, centrándose en publicaciones revisadas por pares que discutieran terapias combinadas o sinérgicas.
Resultados: el trasplante de células madre y el entrenamiento de rehabilitación mejoran la recuperación motora, el recrecimiento axonal, la reconfiguración sináptica y la terapia específica de tareas, mientras que los factores neurotróficos y los andamios bioingenierizados mejoran la reparación endógena.
Conclusión: la rehabilitación regenerativa representa un cambio de paradigma en el tratamiento de la LME, al combinar el potencial reparador de la medicina regenerativa con los beneficios potenciadores de la plasticidad propios de la rehabilitación. Para que estos enfoques combinados continúen siendo exitosos, deben optimizarse el momento de intervención, la dosificación y la individualización del tratamiento.
Citas
International perspectives on spinal cord injury [Internet]. [cited 2025 May 15]. Available from: https://www.who.int/publications/i/item/international-perspectives-on-spinal-cord-injury
Behrman AL, Ardolino EM, Harkema SJ. Activity-Based Therapy: From Basic Science to Clinical Application for Recovery After Spinal Cord Injury. J Neurol Phys Ther JNPT. 2017 Jul;41 Suppl 3(Suppl 3 IV STEP Spec Iss):S39–45. https://doi.org/10.1097/NPT.0000000000000184
Cramer SC, Sur M, Dobkin BH, O’Brien C, Sanger TD, Trojanowski JQ, et al. Harnessing neuroplasticity for clinical applications. Brain J Neurol. 2011 Jun;134(Pt 6):1591–609. https://doi.org/10.1093/brain/awr039
Assinck P, Duncan GJ, Hilton BJ, Plemel JR, Tetzlaff W. Cell transplantation therapy for spinal cord injury. Nat Neurosci. 2017 Apr 25;20(5):637–47. https://doi.org/10.1038/nn.4541
Martin R, Sadowsky C, Obst K, Meyer B, McDonald J. Functional Electrical Stimulation in Spinal Cord Injury: Top Spinal Cord Inj Rehabil [Internet]. 2012 [cited 2025 May 15];18(1):28–33. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3584753/. https://doi.org/10.1310/sci1801-28
Patil N, Korenfeld O, Scalf RN, Lavoie N, Huntemer-Silveira A, Han G, et al. Electrical stimulation affects the differentiation of transplanted regionally specific human spinal neural progenitor cells (sNPCs) after chronic spinal cord injury. Stem Cell Res Ther [Internet]. 2023 Dec 20 [cited 2025 May 15];14:378. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10734202/ https://doi.org/10.1186/s13287-023-03597-w
Silva NA, Sousa N, Reis RL, Salgado AJ. From basics to clinical: a comprehensive review on spinal cord injury. Prog Neurobiol. 2014 Mar;114:25–57. https://doi.org/10.1016/j.pneurobio.2013.11.002
Lu P, Wang Y, Graham L, McHale K, Gao M, Wu D, et al. Long-distance growth and connectivity of neural stem cells after severe spinal cord injury. Cell. 2012 Sep 14;150(6):1264–73. https://doi.org/10.1016/j.cell.2012.08.020
van den Brand R, Heutschi J, Barraud Q, DiGiovanna J, Bartholdi K, Huerlimann M, et al. Restoring voluntary control of locomotion after paralyzing spinal cord injury. Science. 2012 Jun 1;336(6085):1182–5. https://doi.org/10.1126/science.1217416
Curt A, Van Hedel HJA, Klaus D, Dietz V, EM-SCI Study Group. Recovery from a spinal cord injury: significance of compensation, neural plasticity, and repair. J Neurotrauma. 2008 Jun;25(6):677–85. https://doi.org/10.1089/neu.2007.0468
Tam RY, Fuehrmann T, Mitrousis N, Shoichet MS. Regenerative Therapies for Central Nervous System Diseases: a Biomaterials Approach. Neuropsychopharmacology [Internet]. 2014 Jan [cited 2025 May 15];39(1):169–88. Available from: https://www.nature.com/articles/npp2013237 https://doi.org/10.1038/npp.2013.237
Stewart AN, Gensel JC, Jones L, Fouad K. Challenges in Translating Regenerative Therapies for Spinal Cord Injury. Top Spinal Cord Inj Rehabil [Internet]. 2023 [cited 2025 May 15];29(Suppl):23–43. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10759906/ https://doi.org/10.46292/sci23-00044S
Sterne JAC, Savovi? J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019 Aug 28;366:l4898. https://doi.org/10.1136/bmj.l4898
Hooijmans CR, Rovers MM, de Vries RBM, Leenaars M, Ritskes-Hoitinga M, Langendam MW. SYRCLE’s risk of bias tool for animal studies. BMC Med Res Methodol. 2014 Mar 26;14:43. https://doi.org/10.1186/1471-2288-14-43
Moritz CT, Ambrosio F. Regenerative Rehabilitation: Combining Stem Cell Therapies and Activity Dependent Stimulation. Pediatr Phys Ther Off Publ Sect Pediatr Am Phys Ther Assoc [Internet]. 2017 Jul [cited 2025 May 15];29(Suppl 3 IV STEP 2016 CONFERENCE PROCEEDINGS):S10–5. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5488706/ https://doi.org/10.1097/PEP.0000000000000378
Ito A, Kubo N, Liang N, Aoyama T, Kuroki H. Regenerative Rehabilitation for Stroke Recovery by Inducing Synergistic Effects of Cell Therapy and Neurorehabilitation on Motor Function: A Narrative Review of Pre-Clinical Studies. Int J Mol Sci [Internet]. 2020 Jan [cited 2025 May 15];21(9):3135. Available from: https://www.mdpi.com/1422-0067/21/9/3135 https://doi.org/10.3390/ijms21093135
Mancuso R, Santos-Nogueira E, Osta R, Navarro X. Electrophysiological analysis of a murine model of motoneuron disease. Clin Neurophysiol Off J Int Fed Clin Neurophysiol. 2011 Aug;122(8):1660–70. https://doi.org/10.1016/j.clinph.2011.01.045
Tsehay Y, Zeng Y, Weber-Levine C, Awosika T, Kerensky M, Hersh AM, et al. Low-Intensity Pulsed Ultrasound Neuromodulation of a Rodent’s Spinal Cord Suppresses Motor Evoked Potentials. IEEE Trans Biomed Eng [Internet]. 2023 Jul [cited 2025 May 15];70(7):1992–2001. Available from: https://ieeexplore.ieee.org/document/10004722 https://doi.org/10.1109/TBME.2022.3233345
Barker RA, Carpenter MK, Forbes S, Goldman SA, Jamieson C, Murry CE, et al. The Challenges of First-in-Human Stem Cell Clinical Trials: What Does This Mean for Ethics and Institutional Review Boards? Stem Cell Rep [Internet]. 2018 May 8 [cited 2025 May 15];10(5):1429–31. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995446/ https://doi.org/10.1016/j.stemcr.2018.04.010
Oyinbo CA. Secondary injury mechanisms in traumatic spinal cord injury: a nugget of this multiply cascade. Acta Neurobiol Exp (Warsz). 2011;71(2):281–99. https://doi.org/10.55782/ane-2011-1848
Ahuja CS, Nori S, Tetreault L, Wilson J, Kwon B, Harrop J, et al. Traumatic Spinal Cord Injury-Repair and Regeneration. Neurosurgery. 2017 Mar 1;80(3S):S9–22. https://doi.org/10.1093/neuros/nyw080
Sofroniew MV. Astrogliosis. Cold Spring Harb Perspect Biol. 2014 Nov 7;7(2):a020420. https://doi.org/10.1101/cshperspect.a020420
Silver J, Miller JH. Regeneration beyond the glial scar. Nat Rev Neurosci. 2004 Feb;5(2):146–56. https://doi.org/10.1038/nrn1326
Anderson MA, Burda JE, Ren Y, Ao Y, O’Shea TM, Kawaguchi R, et al. Astrocyte scar formation aids central nervous system axon regeneration. Nature. 2016 Apr 14;532(7598):195–200. https://doi.org/10.1038/nature17623
Burda JE, Sofroniew MV. Reactive gliosis and the multicellular response to CNS damage and disease. Neuron. 2014 Jan 22;81(2):229–48. https://doi.org/10.1016/j.neuron.2013.12.034
Liu K, Lu Y, Lee JK, Samara R, Willenberg R, Sears-Kraxberger I, et al. PTEN deletion enhances the regenerative ability of adult corticospinal neurons. Nat Neurosci. 2010 Sep;13(9):1075–81. https://doi.org/10.1038/nn.2603
Sun F, He Z. Neuronal intrinsic barriers for axon regeneration in the adult CNS. Curr Opin Neurobiol. 2010 Aug;20(4):510–8. https://doi.org/10.1016/j.conb.2010.03.013
Filbin MT. Myelin-associated inhibitors of axonal regeneration in the adult mammalian CNS. Nat Rev Neurosci. 2003 Sep;4(9):703–13. https://doi.org/10.1038/nrn1195
Schwab ME. Nogo and axon regeneration. Curr Opin Neurobiol. 2004 Feb;14(1):118–24. https://doi.org/10.1016/j.conb.2004.01.004
Bradbury EJ, Moon LDF, Popat RJ, King VR, Bennett GS, Patel PN, et al. Chondroitinase ABC promotes functional recovery after spinal cord injury. Nature. 2002 Apr 11;416(6881):636–40. https://doi.org/10.1038/416636a
Alilain WJ, Horn KP, Hu H, Dick TE, Silver J. Functional regeneration of respiratory pathways after spinal cord injury. Nature. 2011 Jul 13;475(7355):196–200. https://doi.org/10.1038/nature10199
Angeli CA, Boakye M, Morton RA, Vogt J, Benton K, Chen Y, et al. Recovery of Over-Ground Walking after Chronic Motor Complete Spinal Cord Injury. N Engl J Med. 2018 Sep 27;379(13):1244–50. https://doi.org/10.1056/NEJMoa1803588
Edgerton VR, Harkema S. Epidural stimulation of the spinal cord in spinal cord injury: current status and future challenges. Expert Rev Neurother [Internet]. 2011 Oct [cited 2025 Jun 12];11(10):1351–3. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3361963/ https://doi.org/10.1586/ern.11.129
Cummings BJ, Uchida N, Tamaki SJ, Salazar DL, Hooshmand M, Summers R, et al. Human neural stem cells differentiate and promote locomotor recovery in spinal cord-injured mice. Proc Natl Acad Sci U S A. 2005 Sep 27;102(39):14069–74. https://doi.org/10.1073/pnas.0507063102
Weishaupt N, Blesch A, Fouad K. BDNF: the career of a multifaceted neurotrophin in spinal cord injury. Exp Neurol. 2012 Dec;238(2):254–64. https://doi.org/10.1016/j.expneurol.2012.09.001
Bradbury EJ, Carter LM. Manipulating the glial scar: chondroitinase ABC as a therapy for spinal cord injury. Brain Res Bull. 2011 Mar 10;84(4–5):306–16. https://doi.org/10.1016/j.brainresbull.2010.06.015
Hutchinson KJ, Gómez-Pinilla F, Crowe MJ, Ying Z, Basso DM. Three exercise paradigms differentially improve sensory recovery after spinal cord contusion in rats. Brain J Neurol. 2004 Jun;127(Pt 6):1403–14. https://doi.org/10.1093/brain/awh160
Wagner FB, Mignardot JB, Le Goff-Mignardot CG, Demesmaeker R, Komi S, Capogrosso M, et al. Targeted neurotechnology restores walking in humans with spinal cord injury. Nature. 2018 Nov;563(7729):65–71. https://doi.org/10.1038/s41586-018-0649-2
Donati ARC, Shokur S, Morya E, Campos DSF, Moioli RC, Gitti CM, et al. Long-Term Training with a Brain-Machine Interface-Based Gait Protocol Induces Partial Neurological Recovery in Paraplegic Patients. Sci Rep. 2016 Aug 11;6:30383. https://doi.org/10.1038/srep30383
Johnson KB, Wei W, Weeraratne D, Frisse ME, Misulis K, Rhee K, et al. Precision Medicine, AI, and the Future of Personalized Health Care. Clin Transl Sci [Internet]. 2021 Jan [cited 2025 May 15];14(1):86–93. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877825/ https://doi.org/10.1111/cts.12884
Casha S, Zygun D, McGowan MD, Bains I, Yong VW, Hurlbert RJ. Results of a phase II placebo-controlled randomized trial of minocycline in acute spinal cord injury. Brain J Neurol. 2012 Apr;135(Pt 4):1224–36. https://doi.org/10.1093/brain/aws072
Lima R, Monteiro A, Salgado AJ, Monteiro S, Silva NA. Pathophysiology and Therapeutic Approaches for Spinal Cord Injury. Int J Mol Sci [Internet]. 2022 Nov 10 [cited 2025 May 15];23(22):13833. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9698625/ https://doi.org/10.3390/ijms232213833
Edgerton VR, Tillakaratne NJK, Bigbee AJ, de Leon RD, Roy RR. Plasticity of the spinal neural circuitry after injury. Annu Rev Neurosci. 2004;27:145–67. https://doi.org/10.1146/annurev.neuro.27.070203.144308
Harkema S, Gerasimenko Y, Hodes J, Burdick J, Angeli C, Chen Y, et al. Effect of epidural stimulation of the lumbosacral spinal cord on voluntary movement, standing, and assisted stepping after motor complete paraplegia: a case study. Lancet Lond Engl. 2011 Jun 4;377(9781):1938–47. https://doi.org/10.1016/S0140-6736(11)60547-3
Behrman AL, Ardolino EM, Harkema SJ. Activity-Based Therapy: From Basic Science to Clinical Application for Recovery After Spinal Cord Injury. J Neurol Phys Ther JNPT. 2017 Jul;41 Suppl 3(Suppl 3 IV STEP Spec Iss):S39–45. https://doi.org/10.1097/NPT.0000000000000184
Furlan JC, Kattail D, Fehlings MG. The impact of co-morbidities on age-related differences in mortality after acute traumatic spinal cord injury. J Neurotrauma. 2009 Aug;26(8):1361–7. https://doi.org/10.1177/1545968316644344
Lu DC, Edgerton VR, Modaber M, AuYong N, Morikawa E, Zdunowski S, et al. Engaging Cervical Spinal Cord Networks to Reenable Volitional Control of Hand Function in Tetraplegic Patients. Neurorehabil Neural Repair. 2016 Nov;30(10):951–62. https://doi.org/10.1177/1545968316644344
Turner L. The US Direct-to-Consumer Marketplace for Autologous Stem Cell Interventions. Perspect Biol Med. 2018;61(1):7–24. https://doi.org/10.1353/pbm.2018.0024
Sipp D, Robey PG, Turner L. Clear up this stem-cell mess. Nature. 2018 Sep;561(7724):455–7. https://doi.org/10.1038/d41586-018-06756-9
Hyun I. Allowing innovative stem cell-based therapies outside of clinical trials: ethical and policy challenges. J Law Med Ethics J Am Soc Law Med Ethics. 2010;38(2):277–85. https://doi.org/10.1111/j.1748-720X.2010.00488.x
Kokotilo KJ, Eng JJ, Curt A. Reorganization and Preservation of Motor Control of the Brain in Spinal Cord Injury: A Systematic Review. J Neurotrauma [Internet]. 2009 Nov [cited 2025 May 15];26(11):2113–26. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3167869/ https://doi.org/10.1089/neu.2008.0688
Angeli CA, Boakye M, Morton RA, Vogt J, Benton K, Chen Y, et al. Recovery of Over-Ground Walking after Chronic Motor Complete Spinal Cord Injury. N Engl J Med. 2018 Sep 27;379(13):1244–50. https://doi.org/10.1056/NEJMoa1803588
Tobias IC, Abatti LE, Moorthy SD, Mullany S, Taylor T, Khader N, et al. Transcriptional enhancers: from prediction to functional assessment on a genome-wide scale. Genome. 2021 Apr;64(4):426–48. https://doi.org/10.1139/gen-2020-0104
Capogrosso M, Milekovic T, Borton D, Wagner F, Moraud EM, Mignardot JB, et al. A brain-spine interface alleviating gait deficits after spinal cord injury in primates. Nature. 2016 Nov 10;539(7628):284–8. https://doi.org/10.1038/nature20118
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