Rehabilitation Combined with Neural Progenitor Cell Grafts Enables Functional Recovery in Chronic Spinal Cord Injury

Overview

Journal JCI Insight

Specialties Biomedical Engineering
General Medicine

Date 2022 Aug 22

PMID 35993363

Authors

Paul Lu

Camila M Freria

Lori Graham

Amanda N Tran

Ashley Villarta

Dena Yassin

J Russell Huie

Adam R Ferguson

Mark H Tuszynski

Affiliations

Soon will be listed here.

Abstract

We reported previously that neural progenitor cell (NPC) grafts form neural relays across sites of subacute spinal cord injury (SCI) and support functional recovery. Here, we examine whether NPC grafts after chronic delays also support recovery and whether intensive rehabilitation further enhances recovery. One month after severe bilateral cervical contusion, rats received daily intensive rehabilitation, NPC grafts, or both rehabilitation and grafts. Notably, only the combination of rehabilitation and grafting significantly improved functional recovery. Moreover, improved functional outcomes were associated with a rehabilitation-induced increase in host corticospinal axon regeneration into grafts. These findings identify a critical and synergistic role of rehabilitation and neural stem cell therapy in driving neural plasticity to support functional recovery after chronic and severe SCI.

Citing Articles

Human induced pluripotent stem cell/embryonic stem cell-derived pyramidal neuronal precursors show safety and efficacy in a rat spinal cord injury model.

Li M, Qi B, Li Q, Zheng T, Wang Y, Liu B Cell Mol Life Sci. 2024; 81(1):318.

PMID: 39073571 PMC: 11335242. DOI: 10.1007/s00018-024-05350-9.

Neuromodulation to guide circuit reorganization with regenerative therapies in upper extremity rehabilitation following cervical spinal cord injury.

Balbinot G Front Rehabil Sci. 2024; 4:1320211.

PMID: 38234989 PMC: 10791849. DOI: 10.3389/fresc.2023.1320211.

Resident immune responses to spinal cord injury: role of astrocytes and microglia.

Brockie S, Zhou C, Fehlings M Neural Regen Res. 2023; 19(8):1678-1685.

PMID: 38103231 PMC: 10960308. DOI: 10.4103/1673-5374.389630.

Combining neural progenitor cell transplant and rehabilitation for enhanced recovery after cervical spinal cord injury.

Freria C, Lu P Neural Regen Res. 2023; 19(7):1433-1434.

PMID: 38051883 PMC: 10883491. DOI: 10.4103/1673-5374.387993.

Effects of tail nerve electrical stimulation on the activation and plasticity of the lumbar locomotor circuits and the prevention of skeletal muscle atrophy after spinal cord transection in rats.

Liu J, Chen Z, Wu R, Yu H, Yang S, Xu J CNS Neurosci Ther. 2023; 30(3):e14445.

PMID: 37752787 PMC: 10916423. DOI: 10.1111/cns.14445.

References

Wang L, Conner J, Nagahara A, Tuszynski M . Rehabilitation drives enhancement of neuronal structure in functionally relevant neuronal subsets. Proc Natl Acad Sci U S A. 2016; 113(10):2750-5. PMC: 4790976. DOI: 10.1073/pnas.1514682113. View

Koffler J, Zhu W, Qu X, Platoshyn O, Dulin J, Brock J . Biomimetic 3D-printed scaffolds for spinal cord injury repair. Nat Med. 2019; 25(2):263-269. PMC: 6559945. DOI: 10.1038/s41591-018-0296-z. View

Garcia-Alias G, Barkhuysen S, Buckle M, Fawcett J . Chondroitinase ABC treatment opens a window of opportunity for task-specific rehabilitation. Nat Neurosci. 2009; 12(9):1145-51. DOI: 10.1038/nn.2377. View

Plautz E, Barbay S, Frost S, Zoubina E, Stowe A, Dancause N . Effects of Subdural Monopolar Cortical Stimulation Paired With Rehabilitative Training on Behavioral and Neurophysiological Recovery After Cortical Ischemic Stroke in Adult Squirrel Monkeys. Neurorehabil Neural Repair. 2015; 30(2):159-72. PMC: 4732886. DOI: 10.1177/1545968315619701. View

Jones T, Kleim J, Greenough W . Synaptogenesis and dendritic growth in the cortex opposite unilateral sensorimotor cortex damage in adult rats: a quantitative electron microscopic examination. Brain Res. 1996; 733(1):142-8. DOI: 10.1016/0006-8993(96)00792-5. View

Dulin J, Adler A, Kumamaru H, Poplawski G, Lee-Kubli C, Strobl H . Injured adult motor and sensory axons regenerate into appropriate organotypic domains of neural progenitor grafts. Nat Commun. 2018; 9(1):84. PMC: 5758751. DOI: 10.1038/s41467-017-02613-x. View

Montoya C, Pemberton K, Dunnett S . The "staircase test": a measure of independent forelimb reaching and grasping abilities in rats. J Neurosci Methods. 1991; 36(2-3):219-28. DOI: 10.1016/0165-0270(91)90048-5. View

Coleman W, Geisler F . Injury severity as primary predictor of outcome in acute spinal cord injury: retrospective results from a large multicenter clinical trial. Spine J. 2004; 4(4):373-8. DOI: 10.1016/j.spinee.2003.12.006. View

Poplawski G, Kawaguchi R, Van Niekerk E, Lu P, Mehta N, Canete P . Injured adult neurons regress to an embryonic transcriptional growth state. Nature. 2020; 581(7806):77-82. DOI: 10.1038/s41586-020-2200-5. View

10.

Lepore A, Fischer I . Lineage-restricted neural precursors survive, migrate, and differentiate following transplantation into the injured adult spinal cord. Exp Neurol. 2005; 194(1):230-42. DOI: 10.1016/j.expneurol.2005.02.020. View

11.

Kumar R, Lim J, Mekary R, Rattani A, Dewan M, Sharif S . Traumatic Spinal Injury: Global Epidemiology and Worldwide Volume. World Neurosurg. 2018; 113:e345-e363. DOI: 10.1016/j.wneu.2018.02.033. View

12.

Baska K, Manandhar G, Feng D, Agca Y, Tengowski M, Sutovsky M . Mechanism of extracellular ubiquitination in the mammalian epididymis. J Cell Physiol. 2007; 215(3):684-96. DOI: 10.1002/jcp.21349. View

13.

Bryda E, Pearson M, Agca Y, Bauer B . Method for detection and identification of multiple chromosomal integration sites in transgenic animals created with lentivirus. Biotechniques. 2006; 41(6):715-9. DOI: 10.2144/000112289. View

14.

Lu P, Wang Y, Graham L, McHale K, Gao M, Wu D . Long-distance growth and connectivity of neural stem cells after severe spinal cord injury. Cell. 2012; 150(6):1264-73. PMC: 3445432. DOI: 10.1016/j.cell.2012.08.020. View

15.

Kadoya K, Lu P, Nguyen K, Lee-Kubli C, Kumamaru H, Yao L . Spinal cord reconstitution with homologous neural grafts enables robust corticospinal regeneration. Nat Med. 2016; 22(5):479-87. PMC: 4860037. DOI: 10.1038/nm.4066. View

16.

Whishaw I . Loss of the innate cortical engram for action patterns used in skilled reaching and the development of behavioral compensation following motor cortex lesions in the rat. Neuropharmacology. 2000; 39(5):788-805. DOI: 10.1016/s0028-3908(99)00259-2. View

17.

Bareyre F, Kerschensteiner M, Raineteau O, Mettenleiter T, Weinmann O, Schwab M . The injured spinal cord spontaneously forms a new intraspinal circuit in adult rats. Nat Neurosci. 2004; 7(3):269-77. DOI: 10.1038/nn1195. View

18.

Adler A, Lee-Kubli C, Kumamaru H, Kadoya K, Tuszynski M . Comprehensive Monosynaptic Rabies Virus Mapping of Host Connectivity with Neural Progenitor Grafts after Spinal Cord Injury. Stem Cell Reports. 2017; 8(6):1525-1533. PMC: 5469919. DOI: 10.1016/j.stemcr.2017.04.004. View

19.

Ceto S, Sekiguchi K, Takashima Y, Nimmerjahn A, Tuszynski M . Neural Stem Cell Grafts Form Extensive Synaptic Networks that Integrate with Host Circuits after Spinal Cord Injury. Cell Stem Cell. 2020; 27(3):430-440.e5. PMC: 7484050. DOI: 10.1016/j.stem.2020.07.007. View

20.

Jones T . Motor compensation and its effects on neural reorganization after stroke. Nat Rev Neurosci. 2017; 18(5):267-280. PMC: 6289262. DOI: 10.1038/nrn.2017.26. View