My primary research focuses on gene therapy and neural stem cells for spinal cord injury. My early studies focus on ex vivo gene therapy with neurotrophic factors to promote axonal regeneration into a cell graft placed into the spinal cord lesion site. However, regenerated axons rarely exit from the graft. To enhance axonal exit from the graft, our team uses combinatorial approaches, including modifications of both the injured environment with neurotrophic factors, and intrinsic neuronal growth capacity by alteration of intrinsic neuronal gene expression. Both sensory and motor axons regenerate beyond the lesion site with such an approach. In addition, bridging axons formed synapse with host spinal neurons beyond lesion site, including bridged host supraspinal motor axons cross an upper thoracic complete transection site (Lu et al, 2004; 2012, J. Neurosci.)
Recently, our team develops a new protocol to improve neural stem cell tracking, survival, and differentiation/maturation in the severely injured adult spinal cord by embedding neural stem cells into fibrin matrixes containing growth factor cocktails. This protocol results in retention of neural stem cells and greatly supports their survival within the lesion site as they completely filled the large lesion cavity with a cellular matrix containing great numbers of differentiated neurons. Most remarkably, the grafted neurons extended their axons in remarkable densities and over extraordinary distances in the host spinal cord. This remarkable axonal extension from grafted neurons is consistent in rodent developing central nervous system (CNS) derived neural stem cells, human developing CNS, embryonic stem cells (ESCs), and induced pluripotent stem cells (iPSCs) derived neural stem cell graft. These results indicate that, despite the initial non-growth-supporting environment of the lesioned adult CNS, our protocol transforms the lesion site into one that is highly permissive for growth of neural stem cells. Furthermore, these grafted axons are remyelinated and exhibit extensive synapse formation with host neurons. Host supraspinal axons regenerated into and made synaptic connections with grafted neurons. Thus, grafted neurons could serve as neuronal relays to restore functional connectivity between the injured spinal cord segments. Some of these works are recently published in the Cell and Neuron (Lu et al., 2012, 2014).
1. Neurotrophism without neurotropism: BDNF promotes survival but not growth of lesioned corticospinal neurons. Lu P, Blesch A, Tuszynski MH. The Journal of comparative neurology. 2001; 436(4):456-70.
2. Neurotrophic factors, gene therapy, and neural stem cells for spinal cord repair. Blesch A, Lu P, Tuszynski MH. Brain research bulletin. 2002; 57(6):833-8.
3. NT-3 gene delivery elicits growth of chronically injured corticospinal axons and modestly improves functional deficits after chronic scar resection. Tuszynski MH, Grill R, Jones LL, Brant A, Blesch A, et al. Experimental neurology. 2003; 181(1):47-56.
4. Neural stem cells constitutively secrete neurotrophic factors and promote extensive host axonal growth after spinal cord injury. Lu P, Jones LL, Snyder EY, Tuszynski MH. Experimental neurology. 2003; 181(2):115-29.
5. Combinatorial therapy with neurotrophins and cAMP promotes axonal regeneration beyond sites of spinal cord injury. Lu P, Yang H, Jones LL, Filbin MT, Tuszynski MH. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2004; 24(28):6402-9.
6. Induction of bone marrow stromal cells to neurons: differentiation, transdifferentiation, or artifact? Lu P, Blesch A, Tuszynski MH. Journal of neuroscience research. 2004; 77(2):174-91.
7. BDNF-expressing marrow stromal cells support extensive axonal growth at sites of spinal cord injury. Lu P, Jones LL, Tuszynski MH. Experimental neurology. 2005; 191(2):344-60.
8. Can bone marrow-derived stem cells differentiate into functional neurons? Lu P, Tuszynski MH. Experimental neurology. 2005; 193(2):273-8.
9. Endogenous neurogenesis replaces oligodendrocytes and astrocytes after primate spinal cord injury. Yang H, Lu P, McKay HM, Bernot T, Keirstead H, et al. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2006; 26(8):2157-66.
10. Olfactory ensheathing cells do not exhibit unique migratory or axonal growth-promoting properties after spinal cord injury. Lu P, Yang H, Culbertson M, Graham L, Roskams AJ, et al. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2006; 26(43):11120-30.