Biology subjects

Chesler, A.

Publications and source records attributed to Chesler, A..

5 recordsLinked to original sources

bioRxiv2025

Nociceptors use multiple neurotransmitters to drive pain

Nociceptors are excitatory neurons that express a range of neuropeptides and have the essential role of detecting noxious mechanical, thermal and chemical stimuli. Ablating these neurons profoundly reduces responses to pain. Here we investigated how nociceptive information is transmitted by developing genetic approaches to suppress glutamate transmission and neuropeptide signaling, individually and in combination. Remarkably, many pain responses persisted in mice where either nociceptor glutamate or neuropeptide signaling was blocked. By contrast, mice lacking both glutamate and neuropeptide transmission in nociceptors displayed profound pain insensitivity closely matching the effects of cell ablation. Together our results establish a role for neuropeptides as bone fide pain transmitters and demonstrate redundancy in nociceptor signaling, resolving long-standing questions about how pain is communicated to the brain.

neuroscience↗

bioRxiv2025

Pericyte-tumor crosstalk facilitates metastatic tumor cell latency through PIEZO1-activated lysophospholipid transfer.

Tumor dissemination is increasingly recognized to begin early in tumor development. Although most of these early disseminated cells are cleared, some survive and persist below clinical detection, acting as reservoirs for metastatic relapse. Metastatic tumor cells often rely on interactions with local stromal cells to support their colonization. In this study, we propose that pericyte-tumor cell interactions promote dormancy induction in the early metastatic lung, enhancing disseminated tumor cell (DTC) persistence. Extravital imaging demonstrated that DTCs interact with pericytes upon extravasation into the lung. Co-culture experiments were used to assess DTC fate after pericyte contact and revealed that transient contact with pericytes reduced the proliferation of metastatic 4T1 breast cancer cells but had no effect on non-metastatic 67NR cells. In vivo, transient pericyte contact resulted in higher lung metastatic burden, driven by small, non-proliferative lesions (<6 cells), 10 days after intracardiac injection. These lesions exhibited reduced KI67 staining and EdU incorporation compared to those from monocultured cells. We further observed that primary lung pericytes transferred lyso-phospholipids (lyso-PLs) specifically to metastatic 4T1 cells through direct contact. Gene expression analysis indicated that transient pericyte contact activated pathways related to syncytium formation in metastatic cells. In normal physiology, pericytes act in a syncytium to regulate blood flow via mechanosensitive channels in response to blood pressure changes. We hypothesize that tumor cells exploit these mechanosensitive responses to trigger lyso-PL transfer from pericytes. Supporting this, calcium imaging showed higher calcium activity in pericytes co-cultured with 4T1 cells, and calcium channel inhibitors significantly reduced lyso-PL transfer. Pharmacological activation of pericyte calcium channels induced lyso-PL release, which was subsequently taken up by tumor cells. Conditioned medium from activated pericytes, containing free lyso-PLs, recapitulated the reduced proliferation observed in transient co-culture. Finally, we found our pericyte-induced dormancy signature to be associated with tumor dormancy and distant metastasis free survival latency in breast cancer patients. Together, these findings suggest that early DTCs may exploit pericyte signaling mechanisms to enter dormancy, facilitating their persistence at metastatic sites and contributing to future relapse.

cancer biology↗

bioRxiv2022

Excessive Mechanotransduction in Sensory Neurons Causes Joint Contractures in a Mouse Model of Arthrogryposis

Distal arthrogryposis (DA) is a collection of rare disorders characterized by congenital joint contractures. Most DA mutations are in muscle- and joint-related genes, and the anatomical defects originate cell-autonomously within the musculoskeletal system. However, gain-of-function (GOF) mutations in PIEZO2, a principal mechanosensor in somatosensation, cause DA subtype 5 via unknown mechanisms. We show that expression of a GOF PIEZO2 mutation in proprioceptive sensory neurons mainly innervating muscle spindles and tendons is sufficient to induce DA5-like phenotypes in mice. Overactive PIEZO2 causes anatomical defects via increased activity within the peripheral nervous system during postnatal development. Remarkably, Botox and a dietary fatty acid that modulates PIEZO2 activity markedly reduce DA5-like deficits. This reveals an unexpected role for somatosensory neurons: excessive mechanosensation within these neurons disrupts musculoskeletal development.

neuroscience↗

bioRxiv2020

A spinoparabrachial circuit defined by Tacr1 expression drives pain

Painful stimuli evoke a mixture of sensations, negative emotions and behaviors. These myriad effects are thought to be produced by parallel ascending circuits working in combination. Here we describe a pathway from spinal cord to brain for ongoing pain. Activation of a defined subset of spinal projection neurons expressing Tacr1 evokes a full repertoire of somatotopically-directed coping behaviors in the absence of noxious input. These cells project to a tiny cluster of Tacr1-positive neurons in the superior lateral parabrachial nucleus (PBN-SL) that themselves are responsive to sustained but not acute noxious stimuli. Activation of these PBN-SLTacr1 neurons alone does not trigger pain responses but instead serves to dramatically heighten nocifensive behaviors and suppress itch. Remarkably, mice with silenced PBN-SLTacr1 neurons ignore long-lasting noxious stimuli. These data reveal a spinoparabrachial pathway that plays a key role in the sensation of ongoing pain.

neuroscience↗

bioRxiv2019

HESC-derived sensory neurons reveal an unexpected role for PIEZO2 in nociceptor mechanotransduction

Somatosensation, the detection and transduction of external and internal stimuli, has fascinated scientists for centuries. But still, some of the mechanisms how distinct stimuli are detected and transduced are not entirely understood. Over the past decade major progress has increased our understanding in areas such as mechanotransduction or sensory neuron classification. Additionally, the accessibility to human pluripotent stem cells and the possibility to generate and study human sensory neurons has enriched the somatosensory research field.\n\nBased on our previous work, the generation of functional human mechanoreceptors, we describe here the generation of hESC-derived nociceptor-like cells. We show that by varying the differentiation strategy, we can produce different nociceptive subpopulations. One protocol in particular allowed the generation of a sensory neuron population, homogeneously expressing TRPV1, a prototypical marker for nociceptors. Accordingly, we find the cells to homogenously respond to capsaicin, to become sensitized upon inflammatory stimuli, and to respond to temperature stimulation.\n\nSurprisingly, all of the generated subtypes show mechano-nociceptive characteristics and, quite unexpectedly, loss of mechanotransduction in the absence of PIEZO2.

neuroscience↗