Modeling ALS: Muscle Cells on Demand

Neuromuscular junctions (NMJs) crumble in ALS leading to muscle weakness and paralysis. A growing number of scientists are therefore hoping to identify drugs that stabilize them to help keep muscles moving. However, better protocols may be needed to generate the large number of cells required to create NMJs in vitro for drug discovery purposes.

Go Tubing? Skeletal muscle cells can be produced in large quantities from human iPSCs, that are capable of spontaneous muscle contraction, and can be engrafted into injured muscles – at least in mice. [Courtesy of van der Wal et al., 2018, Stem Cell Reports.]

Now, a research team led by Erasmus University Medical Center’s Pim Pijnappel in the Netherlands reports a transgene-free method to produce skeletal muscle cells from induced pluripotent stem cells (iPSCs) that can be expanded up to 5 × 1011-fold.

The approach comes at the heels of a technique developed by Washington University School of Medicine’s Andrew Yoo in St. Louis, Missouri that enables human motor neurons to be created directly from skin cells – at least from healthy people (see September 2017 news; Abernathy et al., 2017). The strategy is one of a growing number of approaches that aim to streamline the production of these cells to investigate their role in neurodegenerative diseases including ALS and discover potential treatments for them (see September 2017, March 2018 news; Shi et al., 2018).

The protocol is published on May 3 in Stem Cell Reports.

Meanwhile, scientists are developing strategies to recreate NMJs in vitro (see February 2018 news). One strategy, developed by a research team led by University of Central Florida’s J. Hickman, uses a microfluidic system, known as BioMEMs, to help muscles and motor neurons make these connections. The approach creates functional NMJs that can transmit electrical signals, triggering muscle contraction (Santhanam et al., 2018). In future, Hickman’s team, in collaboration with Hesperos in Orlando, Florida, plans to use this approach to identify potential therapies for ALS.  Stay tuned.


To find out about drugs in the ALS pipeline that aim to keep muscles and motor neurons connected, check out Meeting At The ALS Junction.


van der Wal E, Herrero-Hernandez P, Wan R, Broeders M, In ‘t Groen SLM, van Gestel TJM, van IJcken WFJ, Cheung TH, van der Ploeg AT, Schaaf GJ, Pijnappel WWMP. Large-Scale Expansion of Human iPSC-Derived Skeletal Muscle Cells for Disease Modeling and Cell-Based Therapeutic Strategies. Stem Cell Reports. 2018 Apr 28. pii: S2213-6711(18)30154-1. [PubMed].

Abernathy DG, Kim WK, McCoy MJ, Lake AM, Ouwenga R, Lee SW, Xing X, Li D, Lee HJ, Heuckeroth RO, Dougherty JD, Wang T, Yoo AS. MicroRNAs Induce a Permissive Chromatin Environment that Enables Neuronal Subtype-Specific Reprogramming of Adult Human Fibroblasts. Cell Stem Cell. 2017 Sep 7;21(3):332-348.e9. [PubMed].

Shi Y, Lin S, Staats KA, Li Y, Chang WH, Hung ST, Hendricks E, Linares GR, Wang Y, Son EY, Wen X, Kisler K, Wilkinson B, Menendez L, Sugawara T, Woolwine P, Huang M, Cowan MJ, Ge B, Koutsodendris N, Sandor KP, Komberg J, Vangoor VR, Senthilkumar K, Hennes V, Seah C, Nelson AR, Cheng TY, Lee SJ, August PR, Chen JA, Wisniewski N, Hanson-Smith V, Belgard TG, Zhang A, Coba M, Grunseich C, Ward ME, van den Berg LH, Pasterkamp RJ, Trotti D, Zlokovic BV, Ichida JK. Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons. Nat Med. 2018 Mar;24(3):313-325. doi: 10.1038/nm.4490. [PubMed].

Santhanam N, Kumanchik L, Guo X, Sommerhage F, Cai Y, Jackson M, Martin C, Saad G, McAleer CW, Wang Y, Lavado A, Long CJ, Hickman JJ. Stem cell derived phenotypic human neuromuscular junction model for dose response evaluation of therapeutics. Biomaterials. 2018 Jun;166:64-78. [PubMed].



disease-als iMNs induced motor neurons iPSCs motor neuron muscle contraction myogenic progenitor myotube neuromuscular junction NMJ reprogramming stem cell topic-newmethods topic-preclinical
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