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1. Sinopoulou E, Rosenzweig ES, Conner JM, Gibbs D, Weinholtz CA, Weber JL, Brock JH, Nout-Lomas YS, Ovruchesky E, Takashima Y, Biane JS, Kumamaru H, Havton LA, Beattie MS, Bresnahan JC, Tuszynski MH, Rhesus macaque versus rat divergence in the corticospinal projectome, Neuron, 2022.09. |
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Hiromi Kumamaru, Ken Kadoya, Andrew F. Adler, Yoshio Takashima, Lori Graham, Giovanni Coppola, Mark H. Tuszynski, Generation and post-injury integration of human spinal cord neural stem cells, Nature Methods, 10.1038/s41592-018-0074-3, 15, 9, 723-731, 2018.09, Spinal cord neural stem cells (NSCs) have great potential to reconstitute damaged spinal neural circuitry, but they have yet to be generated in vitro. We now report the derivation of spinal cord NSCs from human pluripotent stem cells (hPSCs). Our observations show that these spinal cord NSCs differentiate into a diverse population of spinal cord neurons occupying multiple positions along the dorso-ventral axis, and can be maintained for prolonged time periods. Grafts into injured spinal cords were rich with excitatory neurons, extended large numbers of axons over long distances, innervated their target structures, and enabled robust corticospinal regeneration. The grafts synaptically integrated into multiple host intraspinal and supraspinal systems, including the corticospinal projection, and improved functional outcomes after injury. hPSC-derived spinal cord NSCs could enable a broad range of biomedical applications for in vitro disease modeling and constitute an improved clinically translatable cell source for ‘replacement’ strategies in several spinal cord disorders.. |
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Hiromi Kumamaru, Paul Lu, Ephron S. Rosenzweig, Ken Kadoya, Mark H. Tuszynski, Regenerating Corticospinal Axons Innervate Phenotypically Appropriate Neurons within Neural Stem Cell Grafts, Cell Reports, 10.1016/j.celrep.2019.01.099, 26, 9, 2329-2339.e4, 2019.02, Neural progenitor cell grafts form new relays across sites of spinal cord injury (SCI). Using a panel of neuronal markers, we demonstrate that spinal neural progenitor grafts to sites of rodent SCI adopt diverse spinal motor and sensory interneuronal fates, representing most neuronal subtypes of the intact spinal cord, and spontaneously segregate into domains of distinct cell clusters. Host corticospinal motor axons regenerating into neural progenitor grafts innervate appropriate pre-motor interneurons, based on trans-synaptic tracing with herpes simplex virus. A human spinal neural progenitor cell graft to a non-human primate also received topographically appropriate corticospinal axon regeneration. Thus, grafted spinal neural progenitor cells give rise to a variety of neuronal progeny that are typical of the normal spinal cord; remarkably, regenerating injured adult corticospinal motor axons spontaneously locate appropriate motor domains in the heterogeneous, developing graft environment, without a need for additional exogenous guidance. Kumamaru et al. demonstrate that spinal cord neural progenitor cell grafts spontaneously segregate into motor and sensory domains when implanted into sites of spinal cord injury in rats and primates. Host corticospinal axons regenerating into grafts preferentially regenerate and synapse onto motor interneuron-rich domains, avoiding inappropriate sensory domains.. |
