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      Generation and Expansion of highly-pure Motor Neuron Progenitors from Human Pluripotent Stem Cells

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          SUMMARY

          Human pluripotent stem cells (hPSCs) have opened new opportunities for understanding human development, modeling disease processes and developing new therapeutics. However, these applications are hindered by low-efficiency and heterogeneity of target cell types differentiated from hPSCs, such as motor neurons (MNs), as well as our inability to maintain the potency of lineage committed progenitors. Here, by using a combination of small molecules that regulate multiple signaling pathways, we develop a method to guide human embryonic stem cells to a near-pure population (>95%) of motor neuron progenitors (MNPs) in 12 days, and an enriched population (>90%) of functionally mature MNs in an additional 16 days. More importantly, the MNPs can be expanded for at least 5 passages so that a single MNP can be amplified to 1×10 4. This method is reproducible in human induced pluripotent stem cells and is applied to model MNdegenerative diseases and in proof-of-principle drug screening assays.

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          Induced pluripotent stem cells from a spinal muscular atrophy patient.

          Allison Ebert, Junying Yu, Ferrill F. Rose … (2009)
          Spinal muscular atrophy is one of the most common inherited forms of neurological disease leading to infant mortality. Patients have selective loss of lower motor neurons resulting in muscle weakness, paralysis and often death. Although patient fibroblasts have been used extensively to study spinal muscular atrophy, motor neurons have a unique anatomy and physiology which may underlie their vulnerability to the disease process. Here we report the generation of induced pluripotent stem cells from skin fibroblast samples taken from a child with spinal muscular atrophy. These cells expanded robustly in culture, maintained the disease genotype and generated motor neurons that showed selective deficits compared to those derived from the child's unaffected mother. This is the first study to show that human induced pluripotent stem cells can be used to model the specific pathology seen in a genetically inherited disease. As such, it represents a promising resource to study disease mechanisms, screen new drug compounds and develop new therapies.
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            Directed differentiation of embryonic stem cells into motor neurons.

            Hynek Wichterle, Ivo Lieberam, Jeffery Porter … (2002)
            Inductive signals and transcription factors involved in motor neuron generation have been identified, raising the question of whether these developmental insights can be used to direct stem cells to a motor neuron fate. We show that developmentally relevant signaling factors can induce mouse embryonic stem (ES) cells to differentiate into spinal progenitor cells, and subsequently into motor neurons, through a pathway recapitulating that used in vivo. ES cell-derived motor neurons can populate the embryonic spinal cord, extend axons, and form synapses with target muscles. Thus, inductive signals involved in normal pathways of neurogenesis can direct ES cells to form specific classes of CNS neurons.
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              Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND).

              Robert Miller, J. D. Mitchell, Dan H Moore (2012)
              Riluzole is approved for the treatment of amyotrophic lateral sclerosis in most countries. Questions persist about its clinical utility because of high cost and modest efficacy. To examine the efficacy of riluzole in prolonging survival and in delaying the use of surrogates (tracheostomy and mechanical ventilation) to sustain survival, and to assess the effect of riluzole upon functional health. We searched the Cochrane Neuromuscular Disease Group Specialized Register (20 April 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (2011, Issue 2), MEDLINE (1966 to April 2011), EMBASE (1980 to May 2011) and made enquiries of authors of trials, Aventis (manufacturer of riluzole) and other experts in the field. Types of studies: randomized controlled trials adults with a diagnosis of amyotrophic lateral sclerosis Types of interventions: treatment with riluzole or placebo Types of outcome measures: Primary: pooled hazard ratio of tracheostomy-free survival over all time points with riluzole 100 mg. Secondary: per cent mortality with riluzole 50 mg, 100 mg and 200 mg; neurologic function, muscle strength and adverse events. One author performed data extraction and two other authors checked them. One author checked the data and entered them into the computer. The other authors verified the data entry. We obtained missing data from the trial authors whenever possible. The four trials examining tracheostomy-free survival included a total of 974 riluzole-treated patients and 503 placebo-treated patients. No new randomized controlled trials were found when we updated the searches for this update in 2011. The methodological quality was acceptable and three trials were easily comparable, although one trial (169 participants) included older patients in more advanced stages of amyotrophic lateral sclerosis and one (195 participants) had multiple primary endpoints. Riluzole 100 mg per day provided a benefit for the homogeneous group of patients in the first two trials (hazard ratio (HR) 0.80, 95% confidence internal (CI) 0.64 to 0.99, P= 0.042) and there was no evidence of heterogeneity (P = 0.33). When the third trial (which included older and more seriously affected patients) was added, there was evidence of heterogeneity (P < 0.0001) and the overall treatment effect was reduced but still significant (HR 0.84, 95% CI 0.698 to 0.997, P= 0.046). This represented a 9% gain in the probability of surviving one year (49% in the placebo and 58% in the riluzole group), and increased median survival from 11.8 to 14.8 months. There was a small beneficial effect on both bulbar and limb function, but not on muscle strength. A three-fold increase in serum alanine transferase was more frequent in riluzole-treated patients than controls (mean difference 2.62, 95% CI 1.59 to 4.31). Riluzole 100 mg daily is reasonably safe and probably prolongs median survival by about two to three months in patients with amyotrophic lateral sclerosis.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 101528555
                Journal ID (pubmed-jr-id): 37539
                Journal ID (nlm-ta): Nat Commun
                Journal ID (iso-abbrev): Nat Commun
                Title: Nature communications
                ISSN (Electronic): 2041-1723
                Publication date Nihms-submitted: 16 February 2015
                Publication date (Electronic): 25 March 2015
                Publication date Collection: 2015
                Publication date PMC-release: 25 September 2015
                Volume: 6
                Page: 6626
                Affiliations
                [1 ]Waisman Center, University of Wisconsin, Madison, WI 53705, USA
                [2 ]Department of Rehabilitation Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
                [3 ]Reproductive Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
                [4 ]Promega Corporation, Madison, WI 53711, USA
                [5 ]Department of Neuroscience and Department of Neurology, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705, USA
                Author notes
                [# ]Corresponding author: Zhong-wei Du, PhD, Waisman Center, Rm622, University of Wisconsin, 1500 Highland Avenue, Madison, WI 53705, Phone (608)262-9441, zhongweidu@ 123456wisc.edu . Su-Chun Zhang, MD, PhD, Waisman Center, Rm 651, University of Wisconsin, 1500 Highland Avenue, Madison, WI 53705, Phone: (608) 265-2543, Fax: (608) 890-3479, zhang@ 123456waisman.wisc.edu
                [*]

                These authors contribute equally

                Article
                Manuscript ID: NIHMS663808
                DOI: 10.1038/ncomms7626
                PMC ID: 4375778
                PubMed ID: 25806427
                SO-VID: a6362214-d8a4-43d6-9119-44414e646140
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