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1.
Cell ; 173(1): 153-165.e22, 2018 03 22.
Artículo en Inglés | MEDLINE | ID: mdl-29502968

RESUMEN

CNS injury often severs axons. Scar tissue that forms locally at the lesion site is thought to block axonal regeneration, resulting in permanent functional deficits. We report that inhibiting the generation of progeny by a subclass of pericytes led to decreased fibrosis and extracellular matrix deposition after spinal cord injury in mice. Regeneration of raphespinal and corticospinal tract axons was enhanced and sensorimotor function recovery improved following spinal cord injury in animals with attenuated pericyte-derived scarring. Using optogenetic stimulation, we demonstrate that regenerated corticospinal tract axons integrated into the local spinal cord circuitry below the lesion site. The number of regenerated axons correlated with improved sensorimotor function recovery. In conclusion, attenuation of pericyte-derived fibrosis represents a promising therapeutic approach to facilitate recovery following CNS injury.


Asunto(s)
Cicatriz/patología , Traumatismos de la Médula Espinal/patología , Animales , Axones/fisiología , Axones/efectos de la radiación , Modelos Animales de Enfermedad , Potenciales Evocados/efectos de la radiación , Matriz Extracelular/metabolismo , Fibrosis , Luz , Ratones , Ratones Transgénicos , Pericitos/citología , Pericitos/metabolismo , Estimulación Luminosa , Tractos Piramidales/fisiología , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/genética , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Recuperación de la Función , Regeneración , Corteza Sensoriomotora/fisiología , Traumatismos de la Médula Espinal/fisiopatología
2.
Science ; 383(6683): eade8064, 2024 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-38330107

RESUMEN

Penile erection is mediated by the corpora cavernosa, a trabecular-like vascular bed that enlarges upon vasodilation, but its regulation is not completely understood. Here, we show that perivascular fibroblasts in the corpora cavernosa support vasodilation by reducing norepinephrine availability. The effect on penile blood flow depends on the number of fibroblasts, which is regulated by erectile activity. Erection dynamically alters the positional arrangement of fibroblasts, temporarily down-regulating Notch signaling. Inhibition of Notch increases fibroblast numbers and consequently raises penile blood flow. Continuous Notch activation lowers fibroblast numbers and reduces penile blood perfusion. Recurrent erections stimulate fibroblast proliferation and limit vasoconstriction, whereas aging reduces the number of fibroblasts and lowers penile blood flow. Our findings reveal adaptive, erectile activity-dependent modulation of penile blood flow by fibroblasts.


Asunto(s)
Transportador 1 de Aminoácidos Excitadores , Fibroblastos , Erección Peniana , Pene , Receptores Notch , Animales , Masculino , Ratones , Circulación Sanguínea , Transportador 1 de Aminoácidos Excitadores/metabolismo , Fibroblastos/metabolismo , Fibroblastos/fisiología , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Erección Peniana/fisiología , Pene/irrigación sanguínea , Pene/fisiología , Receptores Notch/metabolismo , Transducción de Señal , Vasoconstricción , Vasodilatación
3.
Nat Neurosci ; 27(7): 1285-1298, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38849523

RESUMEN

Fibrotic scar tissue formation occurs in humans and mice. The fibrotic scar impairs tissue regeneration and functional recovery. However, the origin of scar-forming fibroblasts is unclear. Here, we show that stromal fibroblasts forming the fibrotic scar derive from two populations of perivascular cells after spinal cord injury (SCI) in adult mice of both sexes. We anatomically and transcriptionally identify the two cell populations as pericytes and perivascular fibroblasts. Fibroblasts and pericytes are enriched in the white and gray matter regions of the spinal cord, respectively. Both cell populations are recruited in response to SCI and inflammation. However, their contribution to fibrotic scar tissue depends on the location of the lesion. Upon injury, pericytes and perivascular fibroblasts become activated and transcriptionally converge on the generation of stromal myofibroblasts. Our results show that pericytes and perivascular fibroblasts contribute to the fibrotic scar in a region-dependent manner.


Asunto(s)
Cicatriz , Fibroblastos , Fibrosis , Pericitos , Traumatismos de la Médula Espinal , Animales , Fibroblastos/patología , Fibroblastos/metabolismo , Fibrosis/patología , Traumatismos de la Médula Espinal/patología , Ratones , Pericitos/patología , Pericitos/metabolismo , Masculino , Femenino , Cicatriz/patología , Ratones Endogámicos C57BL , Células del Estroma/patología
4.
Matrix Biol ; 68-69: 561-570, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29428230

RESUMEN

Following lesions to the central nervous system, scar tissue forms at the lesion site. Injury often severs axons and scar tissue is thought to block axonal regeneration, resulting in permanent functional deficits. While scar-forming astrocytes have been extensively studied, much less attention has been given to the fibrotic, non-glial component of the scar. We here review recent progress in understanding fibrotic scar formation following different lesions to the brain and spinal cord. We specifically highlight recent evidence for pericyte-derived fibrotic scar tissue formation, discussing the origin, recruitment, function and therapeutic relevance of fibrotic scarring.


Asunto(s)
Sistema Nervioso Central/patología , Cicatriz/patología , Animales , Encéfalo/patología , Fibrosis , Humanos , Pericitos/patología , Médula Espinal/patología
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