The ultimate goal of this project is to explore cellular and molecular replacement strategies for treating motor neuron degeneration. Our approach entails comprehensive analyses of both intrinsic properties and extrinsic factors that affect the survival of human motor neurons in adult almyotrophic lateral sclerosis (ALS) spinal cord. Our logic is based on the following premises: (1) Motor neuron degeneration in ALS may not be cell autonomous to motor neurons but may arise, in part, from an abnormal glial environment. Thus, modifying the glial environment will protect endogenous motor neurons and create a healthy milieu for grafted motor neurons. (2) We have established a system to efficiently produce healthy human glial cells, such as astrocytes, as well as motor neurons from naive embryonic stem cells (ESCs). These neural cells may represent a source of therapeutic agents, as well as a tool for dissecting neural cell interactions during motor neuron degeneration. (3) Human stem cells, including ESCs and neural stem/progenitor cells, can be genetically modified to carry therapeutic genes. This project will take advantage of advances in our understanding of intermittent hypoxia-induced respiratory motor neuron plasticity under investigation in Project 1, and build upon the foundation of motor neuron-astrocyte interactions in ALS pathogenesis assessed in Project 2. We will genetically modify hESCs (NIH Registry, WA01, WA09) to carry cell death-resistant genes and transplant the differentiated human motor neurons into the spinal cord of ALS rats. Through interactions with projects 1 &2, we will evaluate whether and how intermittent hypoxia, a respiratory exercise, and growth factor-producing astrocytes promote the survival, integration, and axonal growth of the grafted human motor neurons. Our goal is to identify an ideal combinatory strategy to achieve successful transplantation of human motor neurons in the adult ALS spinal cord. Together with projects 1 &2, we hope to arrive at a comprehensive strategy for treating the devastating ALS.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
Project #
Application #
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Cedars-Sinai Medical Center
Los Angeles
United States
Zip Code
Nichols, Nicole L; Satriotomo, Irawan; Allen, Latoya L et al. (2017) Mechanisms of Enhanced Phrenic Long-Term Facilitation in SOD1G93A Rats. J Neurosci 37:5834-5845
Nichols, Nicole L; Mitchell, Gordon S (2016) Quantitative assessment of integrated phrenic nerve activity. Respir Physiol Neurobiol 226:81-6
Jones, Jeffrey R; Zhang, Su-Chun (2016) Engineering human cells and tissues through pluripotent stem cells. Curr Opin Biotechnol 40:133-138
Chen, Hong; Qian, Kun; Chen, Wei et al. (2015) Human-derived neural progenitors functionally replace astrocytes in adult mice. J Clin Invest 125:1033-42
Nikodemova, Maria; Small, Alissa L; Smith, Stephanie M C et al. (2014) Spinal but not cortical microglia acquire an atypical phenotype with high VEGF, galectin-3 and osteopontin, and blunted inflammatory responses in ALS rats. Neurobiol Dis 69:43-53
Gowing, Geneviève; Shelley, Brandon; Staggenborg, Kevin et al. (2014) Glial cell line-derived neurotrophic factor-secreting human neural progenitors show long-term survival, maturation into astrocytes, and no tumor formation following transplantation into the spinal cord of immunocompromised rats. Neuroreport 25:367-72
Dale, E A; Ben Mabrouk, F; Mitchell, G S (2014) Unexpected benefits of intermittent hypoxia: enhanced respiratory and nonrespiratory motor function. Physiology (Bethesda) 29:39-48
Nichols, N L; Johnson, R A; Satriotomo, I et al. (2014) Neither serotonin nor adenosine-dependent mechanisms preserve ventilatory capacity in ALS rats. Respir Physiol Neurobiol 197:19-28
Dale, Erica A; Mitchell, Gordon S (2013) Spinal vascular endothelial growth factor (VEGF) and erythropoietin (EPO) induced phrenic motor facilitation after repetitive acute intermittent hypoxia. Respir Physiol Neurobiol 185:481-8
Nichols, Nicole L; Van Dyke, J; Nashold, L et al. (2013) Ventilatory control in ALS. Respir Physiol Neurobiol 189:429-37

Showing the most recent 10 out of 45 publications