Modeling ALS with motor neurons derived from human induced pluripotent stem cells

Abstract

Directing the differentiation of induced pluripotent stem cells into motor neurons has allowed investigators to develop novel models of ALS. However, techniques vary between laboratories and the cells do not appear to mature into fully functional adult motor neurons. Here we discuss common developmental principles of both lower and upper motor neuron development that have led to specific derivation techniques. We then suggest how these motor neurons may be matured further either through direct expression or administration of specific factors or co-culture approaches with other tissues. Ultimately, through a greater understanding of motor neuron biology, it will be possible to establish more reliable models of ALS. These in turn will have a greater chance of validating new drugs that may be effective for the disease.

Organoid and Organ-on-a-Chip Systems: New Paradigms for Modeling Neurological and Gastrointestinal Disease

“…Utilizing iPSCs to generate neural tissue from patients with neurological diseases at scale can provide a better avenue with which to screen drugs targeting specific human diseases [75]. However, as mentioned above neurons produced in monolayers in the culture dish often lack developmental maturity [76, 77, 51]. Brain-chips taking advantage of unique co-culture geometries have successfully co-cultured human ES cell-derived neural progenitor cells, endothelial cells, mesenchymal stem cells, and microglia/macrophage precursors, allowing complex interactions reminiscent of the developing CNS [78].…”

Uniform‐sized neurosphere‐mediated motoneuron differentiation in microwell arrays

“…Spinal cord lower motoneurons activate skeletal muscle, while corticospinal upper motoneurons connect with spinal cord motoneurons . The degeneration and loss of motoneurons causes the amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy . Although recent studies have been focusing on generating motoneurons in vitro , the use of motoneurons for clinical applications is still limited by the low efficiency of current methods.…”

The challenges of developing a gene therapy for amyotrophic lateral sclerosis

“…Directly addressing these concerns, there have been strides in both the use of in vitro models and efforts to develop other genespecific murine models (e.g. C9orf72 and NEK1) [3,13]. However, one great difficulty is that the symptomology and histology of ALS are not necessarily recapitulated in these models, meaning refinements are necessary [3].…”

“…For example, Yang et al reported the development of SOD1 transgenic pigs that displayed histopathological and symptomatic findings more in parallel with humans [14]. Porcine models also have an established anatomic similarity to the human brain and spine, which is useful in the context of clinical and surgical translation [13]. Overall, the development of topical animal models is progressing rapidly and may provide a space for more robust pre-clinical studies and expanded understanding of the pathophysiology of ALS.…”