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1.
Cell ; 186(16): 3386-3399.e15, 2023 08 03.
Artículo en Inglés | MEDLINE | ID: mdl-37541196

RESUMEN

The gastrointestinal tract is in a state of constant motion. These movements are tightly regulated by the presence of food and help digestion by mechanically breaking down and propelling gut content. Mechanical sensing in the gut is thought to be essential for regulating motility; however, the identity of the neuronal populations, the molecules involved, and the functional consequences of this sensation are unknown. Here, we show that humans lacking PIEZO2 exhibit impaired bowel sensation and motility. Piezo2 in mouse dorsal root, but not nodose ganglia is required to sense gut content, and this activity slows down food transit rates in the stomach, small intestine, and colon. Indeed, Piezo2 is directly required to detect colon distension in vivo. Our study unveils the mechanosensory mechanisms that regulate the transit of luminal contents throughout the gut, which is a critical process to ensure proper digestion, nutrient absorption, and waste removal.


Asunto(s)
Tránsito Gastrointestinal , Canales Iónicos , Mecanotransducción Celular , Animales , Humanos , Ratones , Digestión , Canales Iónicos/metabolismo , Neuronas/metabolismo
2.
Cell ; 184(4): 969-982.e13, 2021 02 18.
Artículo en Inglés | MEDLINE | ID: mdl-33571427

RESUMEN

Iron overload causes progressive organ damage and is associated with arthritis, liver damage, and heart failure. Elevated iron levels are present in 1%-5% of individuals; however, iron overload is undermonitored and underdiagnosed. Genetic factors affecting iron homeostasis are emerging. Individuals with hereditary xerocytosis, a rare disorder with gain-of-function (GOF) mutations in mechanosensitive PIEZO1 ion channel, develop age-onset iron overload. We show that constitutive or macrophage expression of a GOF Piezo1 allele in mice disrupts levels of the iron regulator hepcidin and causes iron overload. We further show that PIEZO1 is a key regulator of macrophage phagocytic activity and subsequent erythrocyte turnover. Strikingly, we find that E756del, a mild GOF PIEZO1 allele present in one-third of individuals of African descent, is strongly associated with increased plasma iron. Our study links macrophage mechanotransduction to iron metabolism and identifies a genetic risk factor for increased iron levels in African Americans.


Asunto(s)
Canales Iónicos/metabolismo , Hierro/metabolismo , Negro o Afroamericano , Envejecimiento/metabolismo , Alelos , Animales , Estudios de Cohortes , Recuento de Eritrocitos , Eritropoyesis , Mutación con Ganancia de Función/genética , Hepatocitos/metabolismo , Hepcidinas/sangre , Hepcidinas/metabolismo , Humanos , Hierro/sangre , Sobrecarga de Hierro/metabolismo , Macrófagos/metabolismo , Mecanotransducción Celular , Ratones Endogámicos C57BL , Fagocitosis , Fenotipo , Estrés Fisiológico
3.
Cell ; 173(2): 443-455.e12, 2018 04 05.
Artículo en Inglés | MEDLINE | ID: mdl-29576450

RESUMEN

Hereditary xerocytosis is thought to be a rare genetic condition characterized by red blood cell (RBC) dehydration with mild hemolysis. RBC dehydration is linked to reduced Plasmodium infection in vitro; however, the role of RBC dehydration in protection against malaria in vivo is unknown. Most cases of hereditary xerocytosis are associated with gain-of-function mutations in PIEZO1, a mechanically activated ion channel. We engineered a mouse model of hereditary xerocytosis and show that Plasmodium infection fails to cause experimental cerebral malaria in these mice due to the action of Piezo1 in RBCs and in T cells. Remarkably, we identified a novel human gain-of-function PIEZO1 allele, E756del, present in a third of the African population. RBCs from individuals carrying this allele are dehydrated and display reduced Plasmodium infection in vitro. The existence of a gain-of-function PIEZO1 at such high frequencies is surprising and suggests an association with malaria resistance.


Asunto(s)
Anemia Hemolítica Congénita/patología , Población Negra/genética , Hidropesía Fetal/patología , Canales Iónicos/genética , Malaria/patología , Alelos , Anemia Hemolítica Congénita/genética , Animales , Deshidratación , Modelos Animales de Enfermedad , Eritrocitos/citología , Eritrocitos/metabolismo , Eliminación de Gen , Genotipo , Humanos , Hidropesía Fetal/genética , Canales de Potasio de Conductancia Intermedia Activados por el Calcio/deficiencia , Canales de Potasio de Conductancia Intermedia Activados por el Calcio/genética , Canales Iónicos/química , Malaria/genética , Malaria/parasitología , Malaria/prevención & control , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fenotipo , Plasmodium berghei/crecimiento & desarrollo , Plasmodium berghei/patogenicidad , Linfocitos T/citología , Linfocitos T/metabolismo
4.
Nature ; 607(7917): 104-110, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35732741

RESUMEN

Itch triggers scratching, a behavioural defence mechanism that aids in the removal of harmful irritants and parasites1. Chemical itch is triggered by many endogenous and exogenous cues, such as pro-inflammatory histamine, which is released during an allergic reaction1. Mechanical itch can be triggered by light sensations such as wool fibres or a crawling insect2. In contrast to chemical itch pathways, which have been extensively studied, the mechanisms that underlie the transduction of mechanical itch are largely unknown. Here we show that the mechanically activated ion channel PIEZO1 (ref. 3) is selectively expressed by itch-specific sensory neurons and is required for their mechanically activated currents. Loss of PIEZO1 function in peripheral neurons greatly reduces mechanically evoked scratching behaviours and both acute and chronic itch-evoked sensitization. Finally, mice expressing a gain-of-function Piezo1 allele4 exhibit enhanced mechanical itch behaviours. Our studies reveal the polymodal nature of itch sensory neurons and identify a role for PIEZO1 in the sensation of itch.


Asunto(s)
Canales Iónicos , Prurito , Alelos , Animales , Canales Iónicos/deficiencia , Canales Iónicos/genética , Canales Iónicos/metabolismo , Ratones , Prurito/genética , Prurito/fisiopatología , Sensación , Células Receptoras Sensoriales/metabolismo
5.
Nature ; 609(7927): 569-574, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-36045288

RESUMEN

Adipose tissues communicate with the central nervous system to maintain whole-body energy homeostasis. The mainstream view is that circulating hormones secreted by the fat convey the metabolic state to the brain, which integrates peripheral information and regulates adipocyte function through noradrenergic sympathetic output1. Moreover, somatosensory neurons of the dorsal root ganglia innervate adipose tissue2. However, the lack of genetic tools to selectively target these neurons has limited understanding of their physiological importance. Here we developed viral, genetic and imaging strategies to manipulate sensory nerves in an organ-specific manner in mice. This enabled us to visualize the entire axonal projection of dorsal root ganglia from the soma to subcutaneous adipocytes, establishing the anatomical underpinnings of adipose sensory innervation. Functionally, selective sensory ablation in adipose tissue enhanced the lipogenic and thermogenetic transcriptional programs, resulting in an enlarged fat pad, enrichment of beige adipocytes and elevated body temperature under thermoneutral conditions. The sensory-ablation-induced phenotypes required intact sympathetic function. We postulate that beige-fat-innervating sensory neurons modulate adipocyte function by acting as a brake on the sympathetic system. These results reveal an important role of the innervation by dorsal root ganglia of adipose tissues, and could enable future studies to examine the role of sensory innervation of disparate interoceptive systems.


Asunto(s)
Tejido Adiposo , Células Receptoras Sensoriales , Tejido Adiposo/inervación , Tejido Adiposo/metabolismo , Tejido Adiposo Beige/inervación , Tejido Adiposo Beige/metabolismo , Animales , Axones , Metabolismo Energético , Ganglios Espinales/fisiología , Homeostasis , Hormonas/metabolismo , Ratones , Especificidad de Órganos , Células Receptoras Sensoriales/fisiología , Grasa Subcutánea/inervación , Grasa Subcutánea/metabolismo , Sistema Nervioso Simpático/citología , Sistema Nervioso Simpático/fisiología , Termogénesis/genética
6.
Science ; 379(6628): 201-206, 2023 01 13.
Artículo en Inglés | MEDLINE | ID: mdl-36634173

RESUMEN

Distal arthrogryposis (DA) is a collection of rare disorders that are 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 mutations in PIEZO2, a principal mechanosensor in somatosensation, cause DA subtype 5 (DA5) through unknown mechanisms. We show that expression of a gain-of-function PIEZO2 mutation in proprioceptive sensory neurons that mainly innervate muscle spindles and tendons is sufficient to induce DA5-like phenotypes in mice. Overactive PIEZO2 causes anatomical defects through increased activity within the peripheral nervous system during postnatal development. Furthermore, botulinum toxin (Botox) and a dietary fatty acid that modulates PIEZO2 activity reduce DA5-like deficits. This reveals a role for somatosensory neurons: Excessive mechanosensation within these neurons disrupts musculoskeletal development.


Asunto(s)
Artrogriposis , Contractura , Canales Iónicos , Mecanotransducción Celular , Células Receptoras Sensoriales , Animales , Ratones , Artrogriposis/genética , Artrogriposis/fisiopatología , Contractura/genética , Contractura/fisiopatología , Mecanotransducción Celular/genética , Mutación , Células Receptoras Sensoriales/fisiología , Canales Iónicos/genética
7.
Neuron ; 111(16): 2488-2501.e8, 2023 08 16.
Artículo en Inglés | MEDLINE | ID: mdl-37321223

RESUMEN

Sensory neurons detect mechanical forces from both the environment and internal organs to regulate physiology. PIEZO2 is a mechanosensory ion channel critical for touch, proprioception, and bladder stretch sensation, yet its broad expression in sensory neurons suggests it has undiscovered physiological roles. To fully understand mechanosensory physiology, we must know where and when PIEZO2-expressing neurons detect force. The fluorescent styryl dye FM 1-43 was previously shown to label sensory neurons. Surprisingly, we find that the vast majority of FM 1-43 somatosensory neuron labeling in mice in vivo is dependent on PIEZO2 activity within the peripheral nerve endings. We illustrate the potential of FM 1-43 by using it to identify novel PIEZO2-expressing urethral neurons that are engaged by urination. These data reveal that FM 1-43 is a functional probe for mechanosensitivity via PIEZO2 activation in vivo and will facilitate the characterization of known and novel mechanosensory processes in multiple organ systems.


Asunto(s)
Canales Iónicos , Mecanotransducción Celular , Ratones , Animales , Mecanotransducción Celular/fisiología , Canales Iónicos/metabolismo , Células Receptoras Sensoriales/fisiología , Compuestos de Piridinio/metabolismo
8.
Elife ; 102021 09 27.
Artículo en Inglés | MEDLINE | ID: mdl-34569935

RESUMEN

Keratinocytes, the predominant cell type of the epidermis, migrate to reinstate the epithelial barrier during wound healing. Mechanical cues are known to regulate keratinocyte re-epithelialization and wound healing; however, the underlying molecular transducers and biophysical mechanisms remain elusive. Here, we show through molecular, cellular, and organismal studies that the mechanically activated ion channel PIEZO1 regulates keratinocyte migration and wound healing. Epidermal-specific Piezo1 knockout mice exhibited faster wound closure while gain-of-function mice displayed slower wound closure compared to littermate controls. By imaging the spatiotemporal localization dynamics of endogenous PIEZO1 channels, we find that channel enrichment at some regions of the wound edge induces a localized cellular retraction that slows keratinocyte collective migration. In migrating single keratinocytes, PIEZO1 is enriched at the rear of the cell, where maximal retraction occurs, and we find that chemical activation of PIEZO1 enhances retraction during single as well as collective migration. Our findings uncover novel molecular mechanisms underlying single and collective keratinocyte migration that may suggest a potential pharmacological target for wound treatment. More broadly, we show that nanoscale spatiotemporal dynamics of Piezo1 channels can control tissue-scale events, a finding with implications beyond wound healing to processes as diverse as development, homeostasis, disease, and repair.


The skin is the largest organ of the body. It enables touch sensation and protects against external insults. Wounding of the skin exposes the body to an increased risk of infection, disease and scar formation. During wound healing, the cells in the topmost layer of the skin, called keratinocytes, move in from the edges of the wound to close the gap. This helps to restore the skin barrier. Previous research has shown that the mechanical forces experienced by keratinocytes play a role in wound closure. Several proteins, called mechanosensors, perceive these forces and instruct the cells what to do. Until now, it was unclear what kind of mechanosensors control wound healing. To find out more, Holt et al. studied a recently discovered mechanosensor (for which co-author Ardem Pataputian received the Nobel Prize in 2021), called Piezo1, using genetically engineered mice. The experiments revealed that skin wounds in mice without Piezo1 in their keratinocytes healed faster than mice with normal levels of Piezo1. In contrast, skin wounds of mice with increased levels of Piezo1 in their keratinocytes healed slower than mice with normal levels of Piezo1. The same pattern held true for keratinocytes grown in the laboratory that had been treated with chemicals to increase the activity of Piezo1. To better understand how Piezo1 slows wound healing, Holt et al. tracked its location inside the keratinocytes. This revealed that the position of Piezo1 changes over time. It builds up near the edge of the wound in some places, and at those regions makes the cells move backwards rather than forwards. In extreme cases, an increased activity of Piezo1 can cause an opening of the wound instead of closing it. These findings have the potential to guide research into new wound treatments. But first, scientists must confirm that blocking Piezo1 would not cause side effects, like reducing the sensation of touch. Moreover, it would be interesting to see if Piezo1 also plays a role in other important processes, such as development or certain diseases.


Asunto(s)
Movimiento Celular , Canales Iónicos/genética , Queratinocitos/fisiología , Transducción de Señal , Cicatrización de Heridas/genética , Animales , Femenino , Canales Iónicos/metabolismo , Masculino , Ratones , Ratones Transgénicos
9.
Sci Transl Med ; 10(462)2018 10 10.
Artículo en Inglés | MEDLINE | ID: mdl-30305457

RESUMEN

The brush of a feather and a pinprick are perceived as distinct sensations because they are detected by discrete cutaneous sensory neurons. Inflammation or nerve injury can disrupt this sensory coding and result in maladaptive pain states, including mechanical allodynia, the development of pain in response to innocuous touch. However, the molecular mechanisms underlying the alteration of mechanical sensitization are poorly understood. In mice and humans, loss of mechanically activated PIEZO2 channels results in the inability to sense discriminative touch. However, the role of Piezo2 in acute and sensitized mechanical pain is not well defined. Here, we showed that optogenetic activation of Piezo2-expressing sensory neurons induced nociception in mice. Mice lacking Piezo2 in caudal sensory neurons had impaired nocifensive responses to mechanical stimuli. Consistently, ex vivo recordings in skin-nerve preparations from these mice showed diminished Aδ-nociceptor and C-fiber firing in response to mechanical stimulation. Punctate and dynamic allodynia in response to capsaicin-induced inflammation and spared nerve injury was absent in Piezo2-deficient mice. These results indicate that Piezo2 mediates inflammation- and nerve injury-induced sensitized mechanical pain, and suggest that targeting PIEZO2 might be an effective strategy for treating mechanical allodynia.


Asunto(s)
Hiperalgesia/metabolismo , Canales Iónicos/metabolismo , Mecanotransducción Celular , Dolor/metabolismo , Potenciales de Acción , Animales , Conducta Animal , Capsaicina , Hiperalgesia/complicaciones , Hiperalgesia/patología , Hiperalgesia/fisiopatología , Canales Iónicos/deficiencia , Ratones Noqueados , Neuronas/metabolismo , Nocicepción , Nociceptores/metabolismo , Dolor/complicaciones , Dolor/patología , Dolor/fisiopatología
10.
Theriogenology ; 98: 108-115, 2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-28601147

RESUMEN

The most common equine breeding practice to decrease the time to the first ovulation of the year is to use artificial lights starting December 1 in the Northern Hemisphere. It can take 60-90 d for this lighting regimen to induce a fertile ovulation. The success rate for pharmaceutical compounds to carry out the same process has been variable. One compound that did induce an early ovulation was recombinant equine follicle stimulating hormone (reFSH), but neither pregnancy nor cyclicity was established in that study. Starting on December 1, 20 deep-anestrous mares of light horse breeds (4-15 y old) with follicles ≤ 20 mm in diameter and progesterone < 1 ng/mL were maintained under natural photoperiod while 10 control mares were maintained under artificial photoperiod. Starting on February 6, treatment mares were randomly assigned to one of two groups: reFSH (n = 10) or reFSH/reLH (n = 10). Jugular blood samples were collected daily from all mares, and luteinizing hormone (LH), FSH, progesterone (P4), estradiol-17ß (E2) and immunoreactive (ir)-inhibin were analyzed by radioimmunoassay (RIA). When the largest follicle reached ≥32 mm in diameter, reFSH treatment was discontinued in both groups while reLH treatment continued in the reFSH/reLH group until a cohort of follicles reached ≥35 mm in diameter. Human chorionic gonadotropin (hCG) was administered intravenously (iv) to induce ovulation, and mares were bred to a fertile stallion every other day until ovulation. Mares receiving either reFSH or reFSH/reLH developed follicles ≥35 mm within 5-6 d of treatment compared with 15.8 ± 3.4 d in the control group. Both reFSH and reFSH/reLH induced ovulation in 100% of the mares within 10 d after treatment resulting in an 80% conception rate and a 70% pregnancy rate for both groups. Conception and pregnancy were designated as either presence of a 14 d old embryo (n = 16) or a fetal heartbeat at 24 d (n = 14), respectively. Only three mares in the control group ovulated within the same treatment period. Later ovulations in the control group resulted in 100% conception and pregnancy rates. At 25 d post-conception, treated mares that were pregnant (n = 7 per group) were administered prostaglandin (PGF2α) to terminate the pregnancy and later returned to estrus. Treatment with reFSH or reFSH/reLH given to deep-anestrous mares under natural photoperiod induced fertile ovulations that resulted in pregnancy and cyclicity when pregnancies were terminated.


Asunto(s)
Hormona Folículo Estimulante/farmacología , Caballos/fisiología , Hormona Luteinizante/farmacología , Ovulación/efectos de los fármacos , Animales , Ciclo Estral/efectos de los fármacos , Ciclo Estral/fisiología , Femenino , Hormona Folículo Estimulante/administración & dosificación , Inseminación Artificial/veterinaria , Hormona Luteinizante/administración & dosificación , Ovulación/fisiología , Fotoperiodo , Embarazo , Proteínas Recombinantes
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