Challenges and Future Prospects on 3D in-vitro Modeling of the Neuromuscular Circuit.

Maider Badiola-Mateos,Josep Samitier,José Antonio Del Río,Arnau Hervera

doi:10.3389/fbioe.2018.00194

Abstract

Movement of skeletal-muscle fibers is generated by the coordinated action of several cells taking part within the locomotion circuit (motoneurons, sensory-neurons, Schwann cells, astrocytes, microglia, and muscle-cells). Failures in any part of this circuit could impede or hinder coordinated muscle movement and cause a neuromuscular disease (NMD) or determine its severity. Studying fragments of the circuit cannot provide a comprehensive and complete view of the pathological process. We trace the historic developments of studies focused on in-vitro modeling of the spinal-locomotion circuit and how bioengineered innovative technologies show advantages for an accurate mimicking of physiological conditions of spinal-locomotion circuit. New developments on compartmentalized microfluidic culture systems (cμFCS), the use of human induced pluripotent stem cells (hiPSCs) and 3D cell-cultures are analyzed. We finally address limitations of current study models and three main challenges on neuromuscular studies: (i) mimic the whole spinal-locomotion circuit including all cell-types involved and the evaluation of independent and interdependent roles of each one; (ii) mimic the neurodegenerative response of mature neurons in-vitro as it occurs in-vivo; and (iii) develop, tune, implement, and combine cμFCS, hiPSC, and 3D-culture technologies to ultimately create patient-specific complete, translational, and reliable NMD in-vitro model. Overcoming these challenges would significantly facilitate understanding the events taking place in NMDs and accelerate the process of finding new therapies.

Highlights

From the physiological and anatomical points of view, the mechanosensory-motor circuit is complex, involving several cell-types with specific natural environments
This review aims to: (i) provide basic insights about the locomotion circuit and neuromuscular diseases required for its in-vitro modeling; (ii) review the breakthrough of bioengineered technologies for neuromuscular-systems; (iii) discuss the limitations and challenges of current study models and future prospects
Spinal MNs cannot achieve proper maturation even after long-term maintenance, unless cultured with muscle-cells, and Schwann cells, as previously reviewed (Bucchia et al, 2018). Both SN and MN could be altered in particular neuromuscular disease (NMD) (Jablonka et al, 2006; Rumsey et al, 2010; Guo et al, 2017), but not being many available studies focused on the muscle spindle (Taylor et al, 2005; Dagberg and Alstermark, 2006; Rumsey et al, 2010; Bewick and Banks, 2015; Matthews, 2015; Guo et al, 2017) challenges the task of mimicking and characterizing the mechanosensory spinal-locomotion circuit

Summary

INTRODUCTION

From the physiological and anatomical points of view, the mechanosensory-motor circuit is complex, involving several cell-types with specific natural environments It has been studied coculturing different cell-types on the same platform from animal origin in 2D (Vilmont et al, 2016; Charoensook et al, 2017; Happe et al, 2017) and 3D (Morimoto et al, 2013; Martin et al, 2015; Smith et al, 2016), or from human origin (Guo et al, 2011; Demestre et al, 2015), In-vitro Approaches for Neuromuscular Diseases or mixed species (Yoshida et al, 2015; Prpar Mihevc et al, 2017). Personalized medicine needs patient-specific isogenic disease models In this regard, human induced pluripotent stem cells (hiPSCs) offer the possibility of obtaining different isogenic cell-types from patient’s somatic cells, by overexpressing some transcription factors (Takahashi and Yamanaka, 2006), later reviewed (Amabile and Meissner, 2009). Osaki et al create an ALS microphysiological 3D in-vitro study-model and compare it with a healthy model (muscle contraction, recovery, and response to drugs administered via endothelial cell barrier)

LIMITATIONS

CONCLUSIONS AND FUTURE