David L. Mack

By Changho Chun, Alec S.T. Smith, Mark Bothwell and David L. Mack

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that impairs motor neuron function, leading to severe muscular atrophy. The non-cell autonomous and heterogeneous nature of the disease has so far hindered attempts to define ALS etiology, leaving the disease incurable and without effective treatments. Recent studies have focused on the pathologic role of intercellular communication between nerve cells to further our understanding of ALS pathophysiology. In this chapter, we summarize recent works investigating the role of extracellular vesicles (EVs) as a means of cellular crosstalk for ALS disease propagation, diagnosis, and treatment. There is growing evidence that EVs secreted by the majority of mammalian cells serve as effective biomolecule carriers to modulate recipient cell behavior. This underscores the need to understand the EV-mediated interplay that occurs within irreversibly degenerating nervous tissue in ALS patients. Additionally, we highlight current gaps in EV-ALS research, especially in terms of the pathologic role and responsibilities of specific EV cargos in diseased cells, specificity issues associated with the use of EVs in ALS diagnosis, and the efficacy of EV-mediated treatments for the restoration of diseased neuromuscular tissue. Finally, we provide suggestions for future EV-ALS research to better understand, diagnose, and cure this inveterate disease.

Part of the book: Amyotrophic Lateral Sclerosis

By Juyoung Seong, Changho Chun, Alec S.T. Smith, Jinmyoung Joo and David L. Mack

Neuromuscular diseases (NMDs) are primarily caused by progressive degeneration of motor neurons that leads to skeletal muscle denervation. The physiological complexity and cellular heterogeneity of individual motor units make understanding the underlying pathological mechanisms of NMDs difficult. Moreover, the demonstrable species specificity of neuromuscular synapse structure and function underscores the need to develop reliable human models of neuromuscular physiology with which to study disease etiology and test the efficacy of novel therapeutics. In this regard, human-induced pluripotent stem cells (hiPSCs) represent a valuable tool for developing such models. However, the lack of cellular diversity and transcriptomic immaturity of motor neurons derived from iPSCs has so far limited their downstream applications. To address this shortcoming, biomaterials such as 3D biopolymer scaffolds and biocompatible nanoparticles have been investigated for their ability to improve current neuronal differentiation protocols. In this review, we summarize current efforts and limitations associated with the use of functional biomaterials to increase the physiological relevance of stem cell-derived motor neurons. We also suggest potential future directions for research using biomaterials to overcome outstanding issues related to stem cell-based neuromuscular tissue production for use in NMD modeling applications.

Part of the book: Motor Neurons