Excitability, the ability to fire action potentials, is a signature feature of neurons. How neurons become excitable during development, and whether excitability is an intrinsic property of neurons or requires signaling from glial cells, remain unclear. Here we demonstrate that Schwann cells, the most abundant glia in the peripheral nervous system, promote somatosensory neuron excitability during development. We find that Schwann cells secrete prostaglandin E2, which is necessary and sufficient to induce somatosensory neurons to express normal levels of voltage-gated sodium channels and fire action potential trains. Inactivating this signaling pathway specifically in Schwann cells selectively impairs nociceptor and proprioceptor somatosensory neuron subtypes, leading to corresponding sensory defects in thermoception, inflammatory pain, and proprioception. Our studies thus reveal a cell non-autonomous mechanism by which glia regulate neuronal excitability to enable the development of normal sensory functions.
Dry age-related macular degeneration (AMD) is estimated to impact nearly 300 million individuals globally by 2040. While no treatment options are currently available, multiple clinical trials investigating retinal pigmented epithelial cells derived from human pluripotent stem cells (hPSC-RPE) as a cellular replacement therapeutic are currently underway. It has been estimated that a production capacity of >109 RPE cells annually would be required to treat the afflicted population, but current manufacturing protocols are limited, being labor-intensive and time-consuming. Microcarrier technology has enabled high-density propagation of many adherent mammalian cell types via monolayer culture on surfaces of uM-diameter matrix spheres; however, few studies have explored microcarrier-based culture of RPE cells. Here, we provide an approach to the growth, maturation, and differentiation of hPSC-RPE cells on Cytodex 1 (C1) and Cytodex 3 (C3) microcarriers. We demonstrate that hPSC-RPE cells adhere to microcarriers coated with Matrigel, vitronectin or collagen, and mature in vitro to exhibit characteristic epithelial cell morphology and pigmentation. Microcarrier-grown hPSC-RPE cells (mcRPE) are viable; metabolically active; express RPE signature genes including BEST1, RPE65, TYRP1, and PMEL17; secrete the trophic factors PEDF and VEGF; and demonstrate phagocytosis of photoreceptor outer segments. Furthermore, we show that undifferentiated hESCs also adhere to Matrigel-coated microcarriers and are amenable to directed RPE differentiation. The capacity to support hPSC-RPE cell cultures using microcarriers enables efficient large-scale production of therapeutic RPE cells sufficient to meet the treatment demands of a large AMD patient population.
Differentiating healthy from pathological aging trajectories is extremely timely, as the global population faces an inversion where older adults will soon outnumber younger 5:1. Many cognitive functions (e.g., memory, executive functions, and processing speed) decline with age, a process that can begin as early as midlife, and which predicts subsequent diagnosis with dementia. Although dementia is a devastating and costly diagnosis, there remains limited evidence for medications, therapies, and devices that improve cognition or attenuate the transition into dementia. There is an urgent need to intervene early in neurodegenerative processes leading to dementia (e.g., depression and mild cognitive impairment). In this targeted review and commentary, we highlight transcutaneous Vagus Nerve Stimulation (tVNS) as a neurostimulation method with unique opportunities for applications in diseases of aging, reviewing recent literature, feasibility of use with remote data collection methods/telehealth, as well as limitations and conflicts in the literature. In particular, small sample sizes, uneven age distributions of participants, lack of standardized protocols, and oversampling of non-representative groups (e.g., older adults with no comorbid diagnoses) limit our understanding of the potential of this method. We offer recommendations for how to improve representativeness, statistical power, and generalizability of tVNS research by integrating remote data collection techniques.
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