Neural Stem Cell Therapy and Rehabilitation in the Central Nervous System: Emerging Partnerships

The goal of regenerative medicine is to restore function through therapy at levels such as the gene, cell, tissue, or organ. For many disorders, however, regenerative medicine approaches in isolation may not be optimally effective. Rehabilitation is a promising adjunct therapy given the beneficial impact that physical activity and other training modalities can offer. Accordingly, “regenerative rehabilitation” is an emerging concentration of study, with the specific goal of improving positive functional outcomes by enhancing tissue restoration following injury. This article focuses on one emerging example of regenerative rehabilitation—namely, the integration of clinically based protocols with stem cell technologies following central nervous system injury. For the purposes of this review, the state of stem cell technologies for the central nervous system is summarized, and a rationale for a synergistic benefit of carefully orchestrated rehabilitation protocols in conjunction with cellular therapies is provided. An overview of practical steps to increase the involvement of physical therapy in regenerative rehabilitation research also is provided.

[1]  D. Fuller,et al.  Delivery of In Vivo Acute Intermittent Hypoxia in Neonatal Rodents to Prime Subventricular Zone-derived Neural Progenitor Cell Cultures. , 2015, Journal of Visualized Experiments.

[2]  J. Peters,et al.  National Institute of Neurological Disorders and Stroke , 2014, Definitions.

[3]  Arun Jayaraman,et al.  Daily intermittent hypoxia enhances walking after chronic spinal cord injury , 2013, Neurology.

[4]  A. Tsukamoto,et al.  Clinical translation of human neural stem cells , 2013, Stem Cell Research & Therapy.

[5]  Michael L. Boninger,et al.  Neuromuscular Electrical Stimulation as a Method to Maximize the Beneficial Effects of Muscle Stem Cells Transplanted into Dystrophic Skeletal Muscle , 2013, PloS one.

[6]  K. Fouad,et al.  Synergistic effects of BDNF and rehabilitative training on recovery after cervical spinal cord injury , 2013, Behavioural Brain Research.

[7]  S. Harkema,et al.  Assessment of functional improvement without compensation reduces variability of outcome measures after human spinal cord injury. , 2012, Archives of physical medicine and rehabilitation.

[8]  V Reggie Edgerton,et al.  Establishing the NeuroRecovery Network: multisite rehabilitation centers that provide activity-based therapies and assessments for neurologic disorders. , 2012, Archives of physical medicine and rehabilitation.

[9]  Pavel Musienko,et al.  Multi-system neurorehabilitative strategies to restore motor functions following severe spinal cord injury , 2012, Experimental Neurology.

[10]  R. Bellamkonda,et al.  Toward a convergence of regenerative medicine, rehabilitation, and neuroprosthetics. , 2011, Journal of neurotrauma.

[11]  Scotty J Butcher,et al.  The First Physical Therapy Summit on Global Health: Implications and Recommendations for the 21st century , 2011, Physiotherapy theory and practice.

[12]  W. Rymer,et al.  Exposure to Acute Intermittent Hypoxia Augments Somatic Motor Function in Humans With Incomplete Spinal Cord Injury , 2011, Neurorehabilitation and neural repair.

[13]  M. Munin,et al.  Inpatient rehabilitation challenges in a quadrimembral amputee after bilateral hand transplantation. , 2011, American journal of physical medicine & rehabilitation.

[14]  M. Fehlings,et al.  A systematic review of cellular transplantation therapies for spinal cord injury. , 2011, Journal of neurotrauma.

[15]  J. Gerring A case study , 2011, Technology and Society.

[16]  Christie K. Ferreira,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 , 2011, The Lancet.

[17]  T. Conlon,et al.  Pompe disease gene therapy. , 2011, Human molecular genetics.

[18]  B. Reynolds,et al.  Acute intermittent hypoxia alters cell fate choice in postnatal neural precursors , 2011 .

[19]  Justin C. Sanchez,et al.  A Symbiotic Brain-Machine Interface through Value-Based Decision Making , 2011, PloS one.

[20]  J. Guest,et al.  Technical aspects of spinal cord injections for cell transplantation. Clinical and translational considerations , 2011, Brain Research Bulletin.

[21]  M. Boninger,et al.  The Emerging Relationship Between Regenerative Medicine and Physical Therapeutics , 2010, Physical Therapy.

[22]  M. Rodgers,et al.  The Physical Therapy and Society Summit (PASS) Meeting: Observations and Opportunities , 2010, Physical Therapy.

[23]  K. Jin,et al.  Transgenic ablation of doublecortin-expressing cells suppresses adult neurogenesis and worsens stroke outcome in mice , 2010, Proceedings of the National Academy of Sciences.

[24]  B. Preston,et al.  Case Series , 2010, Toxicologic pathology.

[25]  R. Sidman,et al.  Communication via gap junctions underlies early functional and beneficial interactions between grafted neural stem cells and the host , 2010, Proceedings of the National Academy of Sciences.

[26]  M. Boninger,et al.  The synergistic effect of treadmill running on stem-cell transplantation to heal injured skeletal muscle. , 2010, Tissue engineering. Part A.

[27]  J. Shumsky,et al.  Forced exercise as a rehabilitation strategy after unilateral cervical spinal cord contusion injury. , 2009, Journal of neurotrauma.

[28]  A. Behrman,et al.  Spinal Cord: Repair and Rehabilitation , 2009 .

[29]  D. Bonatto,et al.  Differentiation of human adipose-derived adult stem cells into neuronal tissue: does it work? , 2009, Differentiation; research in biological diversity.

[30]  D. Steindler,et al.  Bromodeoxyuridine Induces Senescence in Neural Stem and Progenitor Cells , 2008, Stem cells.

[31]  Mingxu,et al.  Functional Integration of Newly Generated Neurons Into Striatum After Cerebral Ischemia in the Adult Rat Brain , 2008 .

[32]  M. Carlén,et al.  Spinal Cord Injury Reveals Multilineage Differentiation of Ependymal Cells , 2008, PLoS biology.

[33]  A. Behrman,et al.  Locomotor Training Restores Walking in a Nonambulatory Child With Chronic, Severe, Incomplete Cervical Spinal Cord Injury , 2008, Physical Therapy.

[34]  N. Theodore,et al.  Stem cell biology and its therapeutic applications in the setting of spinal cord injury , 2008 .

[35]  Richard T. Lee,et al.  Stem-cell therapy for cardiac disease , 2008, Nature.

[36]  T. Origitano,et al.  Thirty-year follow-up after extracranial-intracranial bypass surgery. , 2008, Neurosurgical focus.

[37]  K. Houkin,et al.  Therapeutic Benefits by Human Mesenchymal Stem Cells (hMSCs) and Ang-1 Gene-Modified hMSCs after Cerebral Ischemia , 2008, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[38]  Arun Jayaraman,et al.  Locomotor Training and Muscle Function After Incomplete Spinal Cord Injury: Case Series , 2008, The journal of spinal cord medicine.

[39]  Stephen F Badylak,et al.  The extracellular matrix as a biologic scaffold material. , 2007, Biomaterials.

[40]  Susan J Harkema,et al.  Physical rehabilitation as an agent for recovery after spinal cord injury. , 2007, Physical medicine and rehabilitation clinics of North America.

[41]  R. Sidman,et al.  Physical activity-mediated functional recovery after spinal cord injury: potential roles of neural stem cells. , 2006, Regenerative medicine.

[42]  S. Yamanaka,et al.  Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors , 2006, Cell.

[43]  H. Okano,et al.  Subventricular Zone-Derived Neuroblasts Migrate and Differentiate into Mature Neurons in the Post-Stroke Adult Striatum , 2006, The Journal of Neuroscience.

[44]  D. Steindler,et al.  Fusion of neural stem cells in culture , 2006, Experimental Neurology.

[45]  Henrik Ahlenius,et al.  Persistent Production of Neurons from Adult Brain Stem Cells During Recovery after Stroke , 2006, Stem cells.

[46]  Fred H. Gage,et al.  Exercise Enhances Learning and Hippocampal Neurogenesis in Aged Mice , 2005, The Journal of Neuroscience.

[47]  Jonas Frisén,et al.  Allodynia limits the usefulness of intraspinal neural stem cell grafts; directed differentiation improves outcome , 2005, Nature Neuroscience.

[48]  E. Snyder,et al.  Differentiation and tropic/trophic effects of exogenous neural precursors in the adult spinal cord , 2004, The Journal of comparative neurology.

[49]  P. Reier Cellular transplantation strategies for spinal cord injury and translational neurobiology , 2004, NeuroRX.

[50]  Laurenz Wiskott,et al.  Functional significance of adult neurogenesis , 2004, Current Opinion in Neurobiology.

[51]  Jack M Parent,et al.  Rat forebrain neurogenesis and striatal neuron replacement after focal stroke , 2002, Annals of neurology.

[52]  S. Wolf,et al.  Thirty-third Mary McMillan Lecture: "Look forward, walk tall": Exploring our "What if" questions. , 2002, Physical therapy.

[53]  O. Lindvall,et al.  Neuronal replacement from endogenous precursors in the adult brain after stroke , 2002, Nature Medicine.

[54]  Kozo Nakamura,et al.  Proliferation of Parenchymal Neural Progenitors in Response to Injury in the Adult Rat Spinal Cord , 2001, Experimental Neurology.

[55]  B. Uthman,et al.  Feasibility and safety of neural tissue transplantation in patients with syringomyelia. , 2001, Journal of neurotrauma.

[56]  B. Uthman,et al.  Neurophysiological assessment of the feasibility and safety of neural tissue transplantation in patients with syringomyelia. , 2001, Journal of neurotrauma.

[57]  M. Chopp,et al.  Therapeutic benefit of intracerebral transplantation of bone marrow stromal cells after cerebral ischemia in rats , 2001, Journal of the Neurological Sciences.

[58]  P. Black,et al.  Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[59]  T. F. O'Brien,et al.  Multipotent Stem/Progenitor Cells with Similar Properties Arise from Two Neurogenic Regions of Adult Human Brain , 1999, Experimental Neurology.

[60]  F. Gage,et al.  Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus , 1999, Nature Neuroscience.

[61]  F. Gage,et al.  Neurogenesis in the adult human hippocampus , 1998, Nature Medicine.

[62]  Neal S. Berke,et al.  Repair and Rehabilitation , 1997 .

[63]  F. Gage,et al.  More hippocampal neurons in adult mice living in an enriched environment , 1997, Nature.

[64]  J. Nicholls,et al.  Regeneration of immature mammalian spinal cord after injury , 1996, Trends in Neurosciences.

[65]  S. Hockfield,et al.  The Divergent Homeobox Gene PBX1 Is Expressed in the Postnatal Subventricular Zone and Interneurons of the Olfactory Bulb , 1996, The Journal of Neuroscience.

[66]  S. Badylak,et al.  The use of xenogeneic small intestinal submucosa as a biomaterial for Achilles tendon repair in a dog model. , 1995, Journal of biomedical materials research.

[67]  S. Weiss,et al.  Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. , 1992, Science.

[68]  Scott T. Grafton,et al.  Transplantation of human fetal dopamine cells for Parkinson's disease. Results at 1 year. , 1990, Archives of neurology.

[69]  P. Reier NEURAL TISSUE GRAFTS AND REPAIR OF THE INJURED SPINAL CORD , 1985, Neuropathology and applied neurobiology.

[70]  M. A. Matthews,et al.  An electron microscopic analysis of abnormal ependymal cell proliferation and envelopment of sprouting axons following spinal cord transection in the rat , 1979, Acta Neuropathologica.

[71]  J. Altman Autoradiographic and histological studies of postnatal neurogenesis. IV. Cell proliferation and migration in the anterior forebrain, with special reference to persisting neurogenesis in the olfactory bulb , 1969, The Journal of comparative neurology.

[72]  J. Altman,et al.  Post-Natal Origin of Microneurones in the Rat Brain , 1965, Nature.

[73]  J. Altman,et al.  Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats , 1965, The Journal of comparative neurology.

[74]  J. Altman Autoradiographic investigation of cell proliferation in the brains of rats and cats , 1963, The Anatomical record.

[75]  G. ELLIOT SMITH,et al.  The New Vision , 1928, Nature.

[76]  Hsin-Chieh Yeh,et al.  Effect of the 2011 vs 2003 duty hour regulation-compliant models on sleep duration, trainee education, and continuity of patient care among internal medicine house staff: a randomized trial. , 2013, JAMA internal medicine.

[77]  Michael L Boninger,et al.  Guest editorial: emergent themes from second annual symposium on regenerative rehabilitation, Pittsburgh, Pennsylvania. , 2013, Journal of rehabilitation research and development.

[78]  Candy Tefertiller,et al.  Efficacy of rehabilitation robotics for walking training in neurological disorders: a review. , 2011, Journal of rehabilitation research and development.

[79]  Fabrisia Ambrosio,et al.  Regenerative rehabilitation: a call to action. , 2010, Journal of rehabilitation research and development.

[80]  C. Mason,et al.  A brief definition of regenerative medicine. , 2008, Regenerative medicine.

[81]  M. Fehlings,et al.  Current status of experimental cell replacement approaches to spinal cord injury. , 2008, Neurosurgical focus.

[82]  C. Svendsen,et al.  ENCYCLOPEDIA OF STEM CELL RESEARCH , 2008 .

[83]  Catherine M. Verfaillie,et al.  Pluripotency of mesenchymal stem cells derived from adult marrow , 2007, Nature.

[84]  B. Christie,et al.  Environmental enrichment and voluntary exercise massively increase neurogenesis in the adult hippocampus via dissociable pathways , 2006, Hippocampus.

[85]  P. Reier,et al.  Degeneration, Regeneration, and Plasticity in the Nervous System , 2003 .

[86]  F. Gage,et al.  Isolation, characterization, and use of stem cells from the CNS. , 1995, Annual review of neuroscience.

[87]  J. Nicholls,et al.  Restoration of conduction and growth of axons through injured spinal cord of neonatal opossum in culture. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[88]  Scott T. Grafton,et al.  Therapeutic effects of human fetal dopamine cells transplanted in a patient with Parkinson's disease. , 1990, Progress in brain research.

[89]  Robert C. Wolpert,et al.  A Review of the , 1985 .

[90]  D. Hay,et al.  Call for action. , 1971, Nursing mirror and midwives journal.