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Cell Transplantation to the Rescue: Repairing the Injured Spinal Cord

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Cell Transplantation to the Rescue: Repairing the Injured Spinal Cord Cell transplantation to the rescue: Repairing the injured spinal cord Mary Bartlett Bunge, PhD Christine E. Lynn Distinguished Professor of Neuroscience Professor of Cell Biology, Neurological Surgery, and Neurology The Miami Project to Cure Paralysis® University of Miami Miller School of Medicine [email protected] Founders (1985) Current Staff -Barth Green, M.D. - 21 basic science faculty -Donald Misner - 16 clinical science faculty -Beth Roscoe - 12 management -Nick Buoniconti - 18 post-docs -Marc Buoniconti - 17 graduate students - 104 research staff Scientific Directors - 41 support staff -ÅkeSeiger, M.D., Ph.D. - other students (high -Richard Bunge, M.D. school, undergrad, -W. Dalton Dietrich, Ph.D. medical, residents) Spinal Cord Injury (SCI) • 12,000 new cases / year in the U.S. • Approx 1.275 million Americans with paralysis due to SCI; 5.3 million with paralysis due to some type of CNS injury/disorder • Nearly 50%, ages 16-30; 80%,males • Higher occurrence in military, Dept of Defense funding • MVAs (36.5%), falls (28.5), violence (14) Quality of Life Issues with SCI Muscle paralysis, loss of feeling Reduced pulmonary function Early cardiovascular disease, stroke, DVTs Lack of bowel and bladder control; infection Temperature, blood pressure vary widely Pressure ulcers, osteoporosis Sexual function/fertility impaired Pain long–term, 80 % Obesity, diabetes, cognitive decline Cultured cells for CNS repair “If we have normal cell types available in culture and if a nervous system disease stems from an absence or deficiency of one of these cell types, then it is an obvious step to transfer cultured cells into the diseased animal to attempt to correct the deficiency. Whereas at present this would not seem practical for many types of neurons, it may be practical for supporting cells (e.g. Schwann or glial).” Richard P Bunge, The changing uses of nerve tissue culture 1950-1975 in The Nervous System, Donald B Tower, editor in chief, Vol 1 the Basic Neurosciences, 1975. Nerve cell (neuron) Peripheral nerve Peripheral nerve Schwann cell myelinated axons Myelin formation by Schwann cells Albert J. Aguayo, M.D. Photo of St. Louis Arch Patrick M. Wood, PhD Schwann cell biology in vitro • SCs generate a number of ECM components • SCs require contact with ECM to differentiate • SCs require contact with axons to form basal lamina • SCs require basal lamina to form myelin • SCs require ascorbic acid to form myelin (Type IV collagen) [Defined medium (N2) supported SC profileration but not differentiation] Schwann cell biology in vitro - 2 • Mitogenic signal on axons for SC proliferation (control of SC #) • Perineurium formed in cultures of neurons, SCs and fibroblasts • Perineurium formed from fibroblasts, not SCs (Lac-Z retrovirus) • Circumnavigation by inner lip of SC cytoplasm a part of myelin formation mechanism Why Schwann cells? • Promote axon regeneration/PN • Aguayo team; CNS axons regenerated into PN • Are readily accessible in PN • Produce growth factors, ECM • Myelinate axons in CNS, restore activity • Can obtain large numbers in culture • Can transplant person’s own cells • Can genetically engineer cells • Promising pre-clinical data in multiple species (rats, pigs, primates) ; FDA approval for human SCs Xiao-Ming Xu, M.D., Ph.D. Xu XM, Guénard V, Kleitman N, Bunge MB (1995) Axonal regeneration into Schwann cell-seeded guidance channels grafted into transected adult rat spinal cord. J Comp Neurol 351:145-160. Xu XM, Guénard V, Kleitman N, Aebischer P, Bunge MB (1995) A combination of BDNF and NT-3 promotes supraspinal axonal regeneration into Schwann cell grafts in adult rat thoracic spinal cord. Exp Neurol 134:261-272. Xu XM, Chen A, Guénard V, Kleitman N, Bunge MB (1997) Bridging Schwann cell transplants promote axonal regeneration from both the rostral and caudal stumps of transected adult rat spinal cord. J Neurocytol 26:1-16. PAN/PVC tube * SC Scanning EM How do we measure outcome? -Behavior: Walking? Pain assessment? -Histology: Lesion volume, overall tissue changes -Transplanted SC survival and number? -Count SC-myelinated axons? Total # axons? -Immunostaining Scar formation? Types of axons in implant, and beyond? Inflammatory response? -Neuroanatomical tracing What spinal and supraspinal neurons responded? What types of axons regenerated into implant? Did these axons leave implant? SC/Matrigel bridge at 30 dpt Thoracic complete transection model: Schwann cells • Axons grow onto SC bridge from both stumps • 2000 myelinated axons on bridge • 8x more non-myelinated axons/bridge Transplants at 12 wk after contusion injury LV-GFP Dr. Damien Pearse Thoracic contusion model: Schwann cells • Reduce cyst formation • Protect spinal cord tissue from secondary damage • Support axonal growth into SC graft • ~5000 SC-myelinated axons in graft • Some improvement in walking after paralysis Injured spinal cord tissue environment -1 • Excessive EAA (e.g., glutamate) release • EAA receptor activation • Excessive Ca++ entry into cells • Ca++ stimulated activation of proteolytic and other degradative enzymes • Cytoskeletal protein breakdown • Oxygen free radical release leading to membrane damage • Cytokine, chemokine release Injured spinal cord tissue environment-2 • Many tissue damaging sequelae initiated, leading to secondary damage • Substances inhibitory to repair appear • Inflammation begins • Barrier to axon growth (scar) forms • Sustenance for surviving nerve cells cut off • Cyst created due to tissue loss, preventing axon regrowth To repair the cord - 1 • Halt spread of secondary tissue damage • Save as many nerve cells as possible • Curb inflammation • Reduce scar formation • Neutralize inhibitory factors To repair the cord - 2 • Awaken nerve cells to regrow axons • Provide sustenance to nerve cells • Promote axon growth across injury • Guide growth to appropriate area • Enable formation of connections Combination strategies: SCs + • Steroid (used clinically) • Variety of growth factors • Another cell type (olfactory ensheathing cells) • An enzyme (to reduce scar formation) • Elevation of a cell signaling molecule, cAMP • Introduction of genes to improve Schwann cell efficacy ALL THESE IMPROVED REPAIR/FUNCTION Combination strategies: SCs + • More SC-myelinated axons in graft • Increase in regenerated axons from neurons above spinal cord (Distance factor overcome) • Exit of regenerated axons from graft into the cord • More improvement in walking SCs with added growth factor gene survive better and improve axon growth Control SCs SCs + growth factor Viral Vector/growth factor (GF)- engineered SC study (2007) GF levels signif. increased in cord at 2 dpt, low levels up to 6 wpt GF led to 5X increase in graft vol, SC # GF led to a signif. increase in myel. axons (SC 5,100; LV-GFP SCs 4,600; LV-GFP/GF SCS 26,000) and total axons (~75,000) DβH+ fiber length signif. increased with GF No improvement in walking Combined engineering of Schwann cell implants to secrete neurotrophin and chondroitinase promotes axonal regeneration and locomotion after SCI H Kanno, Y Pressman, A Moody, R Berg, E Muir, J Rogers, H Ozawa, E Itoi, D Pearse, M Bunge Haruo Kanno, M.D., Ph.D. Experiment Adult female Fischer rats (160-180g) • Moderate contusion injury at thoracic 8 level Schwann cell transplantation: • 1 week after injury, 1+1 million cells Experimental groups: 1. Vehicle (no cells) (control) 2. green-SCs + red-SCs (control) 3. green/GF-SCs + red-SCs 4. green-SCs + red/ENZ-SCs 5. green/GF-SCs + red/ENZ-SCs Chondroitinase activity in vivo 2B6 staining GFP mCherry/ChABC 1000μm 2B6 SC-transplanted spinal cord Control Combination strategy SC myelination in implant 80000 DMEM/F12 GFP + mCherry 70000 GFP/GF+ mCherry GFP + mCherry/ChABC GFP/GF + mCherry/ChABC 60000 # 50000 axons /section 40000 * 30000 * 20000 10000 # SC myelinated 0 1) DMEM/F122) GFP +3) mCherry GFP/D15A4) GFP + mCherry +5) mCherry/Ch'ase GFP/D15A + mCherry/Ch'ase Combination vs single treatments • Further increase in implant compared to GF or ENZ • Further increase in SC myel axons compared to ENZ • Higher number of responding neurons above cord than with GF or ENZ • Higher number of their axons in implant and in cord beyond than with GF or ENZ • Improved walking scores • Lessened pain in hindpaws Experimental Neurology 1997;148:502-22 The ability of human Schwann cell grafts to promote regeneration in the transected nude rat spinal cord Guest JD, Rao A, Olson L, Bunge MB, Bunge RP The Miami Project to Cure Paralysis, The Organ Procurement Team, Department of Neurological Surgery, University of Miami School of Medicine, Miami, Florida __________________________________________________________________________ . Nude athymic rats . Human SCs/Matrigel, with or without PAN/PVC channels . T8 complete transection, T9-10 cord removed . Methylprednisolone Myelinated axons, ~2,000 Propriospinal, sensory, motoneuronal, brainstem (DβH, 5HT) axons in SC bridge Propriospinal and sensory axons re-entered the spinal cord (up to 2.6 mm) Walking scores significantly improved __________________________________________________ Robust axon growth into SC bridge, some growth beyond and modest improvement in locomotion Human Schwann cells . Can be isolated and readily increased in # in culture . Up to 10 m SCs, single adult sural nerve biopsy 100 m SCs in 3-4 wk . Variation in rate of increase from donor to donor . Preparation: Careful dissection of bundles Intro culture medium with forskolin (↑cAMP) and heregulin (mitogenic), 1 wk Overnight incubation in collagenase and dispase; then mechanical dissociation
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