Modeling enteric glia development, physiology and disease using human pluripotent stem cells.

Enteric glia play an integral role in many functions of the gastrointestinal (GI) system, but they have not been characterized comprehensively compared to other cells of the gut. Enteric glia are a specialized type of neuroglia in the enteric nervous system (ENS) that support neurons and interact with other cells of the gut such as immune and epithelial cells. The ENS is diffusely spread throughout the GI tract, making it extremely difficult to access and manipulate. As a result, it has remained extremely understudied. Nevertheless, much more is known about enteric neurons than enteric glia despite the glia being 6 times more abundant in humans [1]. In the past two decades, our understanding of enteric glia has greatly expanded and their many roles in the gut have been described and reviewed elsewhere [2-5]. While the field has made substantial progress, there are still a multitude of open questions about enteric glia biology and their role in disease. Many of these questions have remained intractable due to technical limitations of currently available experimental models of the ENS. In this review, we describe the benefits and limitations of the models commonly used to study enteric glia and discuss the ways in which a human pluripotent stem cell (hPSC) derived enteric glia model could help advance the field.

Deriving Schwann cells from hPSCs enables disease modeling and drug discovery for diabetic peripheral neuropathy.

Schwann cells (SCs) are the primary glia of the peripheral nervous system. SCs are involved in many debilitating disorders, including diabetic peripheral neuropathy (DPN). Here, we present a strategy for deriving SCs from human pluripotent stem cells (hPSCs) that enables comprehensive studies of SC development, physiology, and disease. hPSC-derived SCs recapitulate the molecular features of primary SCs and are capable of in vitro and in vivo myelination. We established a model of DPN that revealed the selective vulnerability of SCs to high glucose. We performed a high-throughput screen and found that an antidepressant drug, bupropion, counteracts glucotoxicity in SCs. Treatment of hyperglycemic mice with bupropion prevents their sensory dysfunction, SC death, and myelin damage. Further, our retrospective analysis of health records revealed that bupropion treatment is associated with a lower incidence of neuropathy among diabetic patients. These results highlight the power of this approach for identifying therapeutic candidates for DPN.

Different Inhibitory Interneuron Cell Classes Make Distinct Contributions to Visual Contrast Perception.

While recent work has revealed how different inhibitory interneurons influence responses of cortical neurons to sensory stimuli, little is known about their distinct contributions to sensory perception. Here, we optogenetically activated different genetically defined interneurons [parvalbumin (PV), somatostatin (SST), vasoactive intestinal peptide (VIP)] in visual cortex (V1) of mice working at threshold in a contrast increment detection task. The visual stimulus was paired with optogenetic stimulation to assess how enhancing V1 inhibitory neuron activity during visual processing altered task performance. PV or SST activation impaired, while VIP stimulation improved, contrast increment detection. The impairment produced by PV or SST activation persisted over several weeks of testing. In contrast, mice learned to reliably detect VIP activation in the absence of any natural visual stimulus. Thus, different inhibitory signals make distinct contributions to visual contrast perception.