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Parasympathetic neurons derived from human pluripotent stem cells model human diseases and development

ABSTRACT: Parasympathetic neurons (parasymNs) belong to the autonomic nervous system (ANS) and are critical for unconscious body responses, including rest-and-digest and calming the body. ParasymN dysfunction has been found involved in neural diseases such as autonomic neuropathy and neurological autoimmune disease; and parasymN innervation is important for organ development. However, human parasymN function and dysfunction is vastly understudied, due to the lack of a model system. Human pluripotent stem cell (hPSC)-derived neurons can fill this void and serve for disease modeling, drug screening, and transplantation therapy. Here, we developed a differentiation paradigm detailing for the first time, the derivation of functional human parasymNs from Schwann cell progenitors (SCP). We employ these neurons (i) to assess human ANS development paradigms, (ii) to model neuropathy in the genetic disorder Familial Dysautonomia (FD), (iii) to show parasymN dysfunction during SARS-CoV-2 infection, (iv) to model the autoimmune disease Sjörgen’s syndrome and, (v) to show that parasymN innervation of white adipocytes during development and help mature the tissue. Our model system will become instrumental for future disease mechanistic and drug discovery studies as well as for human developmental studies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE253235 | GEO | 2024/01/15

REPOSITORIES: GEO

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Project description:The cardiac autonomic nervous system is crucial in controlling cardiac function, such as heart rate and cardiac contractility, and is divided into sympathetic and parasympathetic branches. Normally, there is a balance between these two branches to maintain homeostasis. However, cardiac disease states such as myocardial infarction, heart failure, and hypertension can induce the remodeling of cells involved in cardiac innervation, which is associated with an adverse clinical outcome. Although there are vast amounts of data for the histological structure and function of the cardiac autonomic nervous system, its molecular biological architecture in health and disease is still enigmatic in many aspects. Novel technologies such as single-cell RNA sequencing (scRNA-seq) hold promise for the genetic characterization of tissues at single-cell resolution. However, the relatively large size of neurons may impede the standardized use of these techniques. Here, this protocol exploits droplet-based single-nucleus RNA sequencing (snRNA-seq), a method to characterize the biological architecture of cardiac sympathetic neurons in health and disease. A stepwise approach is demonstrated to perform snRNA-seq of the bilateral superior cervical (SCG) and stellate ganglia (StG) dissected from adult mice. This method enables long-term sample preservation, maintaining an adequate RNA quality when samples from multiple individuals/experiments cannot be collected all at once within a short period of time. Barcoding the nuclei with hashtag oligos (HTOs) enables demultiplexing and the trace-back of distinct ganglionic samples post sequencing. Subsequent analyses revealed successful nuclei capture of neuronal, satellite glial, and endothelial cells of the sympathetic ganglia, as validated by snRNA-seq. In summary, this protocol provides a stepwise approach for snRNA-seq of sympathetic extrinsic cardiac ganglia, a method that has the potential for broader application in studies of the innervation of other organs and tissues.

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Parasympathetic neurons derived from human pluripotent stem cells model human diseases and development

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