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2.
Cell Rep ; 42(12): 113459, 2023 12 26.
Artículo en Inglés | MEDLINE | ID: mdl-37988266

RESUMEN

Mesenchymal stem cells (MSCs) are present in almost all the tissues in the body, critical for their homeostasis and regeneration. However, the stemness of MSCs is mainly an in vitro observation, and lacking exclusive markers for endogenous MSCs makes it difficult to study the multipotency of MSCs in vivo, especially for human MSCs. To address this hurdle, we injected GFP-tagged human embryonic stem cell (hESC)-derived MSCs (EMSCs) into mouse blastocysts. EMSCs survived well and penetrated both the inner cell mass and trophectoderm, correlating to the higher anti-apoptotic capability of EMSCs than hESCs. Injected EMSCs contributed to skeletal, dermal, and extraembryonic tissues in the resultant chimera and partially rescued skeletal defects in Sox9+/- mouse fetuses. Thus, this study provides evidence for the stemness and developmental capability of human MSCs through chimerization with the mouse blastocyst, serving as a model for studying human mesenchymal and skeletal development.


Asunto(s)
Células Madre Embrionarias Humanas , Células Madre Mesenquimatosas , Humanos , Ratones , Animales , Diferenciación Celular , Células Madre Embrionarias , Blastocisto
3.
Biomaterials ; 289: 121759, 2022 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-36075143

RESUMEN

We have previously demonstrated that mesenchymal stromal/stem cells (MSCs) in spheroids (MSCsp) tolerate ambient and hypoxic conditions for a prolonged time. Local administration of MSCsp, but not dissociated MSCs (MSCdiss), promotes wound healing and relieves multiple sclerosis and osteoarthritis in mice and monkeys. These findings indicate an advantage of MSCsp over MSCdiss in sustaining cell viability and efficacy following transplantation, which, however, does not appear to apply to intravenous (i.v.) injection for the principal concern that MSCsp might cause embolism in small blood vessels of the host, leading to sudden death. Here, we addressed this concern by injecting human MSCsp (∼450 µm) or MSCdiss i.v. into cynomolgus monkeys. Surprisingly, no deaths occurred until sacrifice at day 21 or 60 post injection, and no remarkable physiological changes were found in the animals following the i.v. injection. The big diameters of large blood vessels in monkeys, compared to small animals like mice, may allow sufficient time for MSCsp to dissociate into single cells so they can pass through small vessels without causing embolism. Retention of MSCsp was lower in the lungs but higher in the blood than retention of MSCdiss at 1 h post injection and both disappeared at day 21. In vitro, MSCsp tolerated fluidic shear stress with higher survival than MSCdiss. Thus, i.v. injection of MSCsp into nonhuman primates is feasible, safe, and probably associated with better survival, less lung entrapment and higher efficacy than administration of MSCdiss.


Asunto(s)
Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Osteoartritis , Animales , Humanos , Inyecciones Intravenosas , Macaca fascicularis , Ratones , Osteoartritis/metabolismo
4.
Cell Death Dis ; 8(3): e2697, 2017 03 23.
Artículo en Inglés | MEDLINE | ID: mdl-28333135

RESUMEN

The BRE (brain and reproductive expression) gene, highly expressed in nervous and reproductive system organs, plays an important role in modulating DNA damage repair under stress response and pathological conditions. Folliculogenesis, a process that ovarian follicle develops into maturation, is closely associated with the interaction between somatic granulosa cell and oocyte. However, the regulatory role of BRE in follicular development remains undetermined. In this context, we found that BRE is normally expressed in the oocytes and granulosa cells from the primordial follicle stage. There was a reduction in follicles number of BRE mutant (BRE-/-) mice. It was attributed to increase the follicular atresia in ovaries, as a result of retarded follicular development. We established that cell proliferation was inhibited, while apoptosis was markedly increased in the granulosa cells in the absence of BRE. In addition, expressions of γ-H2AX (marker for showing DNA double-strand breaks) and DNA damage-relevant genes are both upregulated in BRE-/- mice. In sum, these results suggest that the absence of BRE, deficiency in DNA damage repair, causes increased apoptosis in granulosa cells, which in turn induces follicular atresia in BRE-/- mice.


Asunto(s)
Muerte Celular/fisiología , Atresia Folicular/metabolismo , Células de la Granulosa/metabolismo , Células de la Granulosa/patología , Proteínas del Tejido Nervioso/metabolismo , Proteínas Nucleares/metabolismo , Folículo Ovárico/metabolismo , Ovario/metabolismo , Animales , Apoptosis/fisiología , Línea Celular Tumoral , Proliferación Celular/fisiología , Daño del ADN/fisiología , Reparación del ADN/fisiología , Femenino , Atresia Folicular/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Oocitos/metabolismo , Folículo Ovárico/fisiología
5.
J Agric Food Chem ; 64(7): 1610-7, 2016 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-26843032

RESUMEN

High salt intake has been known to cause hypertension and other side effects. However, it is still unclear whether it also affects fibrosis in the mature or developing liver. This study demonstrates that high salt exposure in mice (4% NaCl in drinking water) and chick embryo (calculated final osmolality of the egg was 300 mosm/L) could lead to derangement of the hepatic cords and liver fibrosis using H&E, PAS, Masson, and Sirius red staining. Meanwhile, Desmin immunofluorescent staining of mouse and chick embryo livers indicated that hepatic stellate cells were activated after the high salt exposure. pHIS3 and BrdU immunohistological staining of mouse and chick embryo livers indicated that cell proliferation decreased; as well, TUNEL analyses indicated that cell apoptosis increased in the presence of high salt exposure. Next, dihydroethidium staining on the cultured chick hepatocytes indicated the excess ROS was generated following high salt exposure. Furthermore, AAPH (a known inducer of ROS production) treatment also induced the liver fibrosis in chick embryo. Positive Nrf2 and Keap1 immunohistological staining on mouse liver suggested that Nrf2/Keap1 signaling was involved in high salt induced ROS production. Finally, the CCK8 assay was used to determine whether or not the growth inhibitory effect induced by high salt exposure can be rescued by antioxidant vitamin C. Meanwhile, the RT-PCR result indicated that the Nrf2/Keap1 downsteam genes including HO-1, NQO-1, and SOD2 were involved in this process. In sum, these experiments suggest that high salt intake would lead to high risk of liver damage and fibrosis in both adults and developing embryos. The pathological mechanism may be the result from an imbalance between oxidative stress and the antioxidant system.


Asunto(s)
Cirrosis Hepática/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Cloruro de Sodio/efectos adversos , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Apoptosis , Proliferación Celular , Embrión de Pollo , Proteínas del Citoesqueleto/genética , Proteínas del Citoesqueleto/metabolismo , Hepatocitos/citología , Hepatocitos/metabolismo , Humanos , Proteína 1 Asociada A ECH Tipo Kelch , Cirrosis Hepática/etiología , Cirrosis Hepática/genética , Cirrosis Hepática/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo , Cloruro de Sodio/análisis , Cloruro de Sodio/metabolismo
6.
Placenta ; 36(10): 1087-94, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26282852

RESUMEN

INTRODUCTION: For ectopic tubal pregnancy to be viable, it requires a supporting vascular network and functioning trophoblast. Slit2/Robo1 signaling plays an important role in placental angiogenesis during normal pregnancy. Hence, we here investigated whether or not Slit2/Robo1 signaling also had an impact in ectopic tubal pregnancy. METHODS: The Slit2 and Robo1 expression pattern relevant to trophoblast invasive behavior and vascular remodeling was studied in human tubal placenta obtained from patients with ectopic pregnancy (5-8weeks gestation), The trophoblast development, vascular architecture and Robo1 expression pattern were observed in Slit2 overexpression (Slit2-Tg) and C57BL mice placenta (E13.5 and E15.5). RESULTS: Marked with CK-7 and Vimentin, the vessel profiles of fallopian tube were classified into four stages. In the presence of extravillous trophoblast (EVT), stellate-shaped and polygonal-shaped EVTs were observed, and the stellate-shaped EVT showed the higher Slit2 expression (P < 0.01) but lower Robo1 expression (P < 0.05) than polygonal-shaped cells. By contrast, a temporary Slit2 up-regulation in remodeling vessel and Slit2 down-regulation in remodeled vessel of polygonal-shape extravillous trophoblast cells occurred in tubal pregnancies. In Slit2-Tg mice E13.5 and E15.5 placenta, Slit2 overexpression promoted vascular remodeling by increasing in the diameter of the maternal blood sinusoids and fetal capillaries, but enhanced the thickness of trophoblast and vasculature at E15.5 Slit2-Tg mice. CONCLUSIONS: The varying Slit2 and Robo1 expression in EVTs was associated with trophoblast invasion and probably plays an important role in the events of blood vessel remodeling of the fallopian tube tissues.


Asunto(s)
Transición Epitelial-Mesenquimal , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Embarazo Tubario/metabolismo , Receptores Inmunológicos/metabolismo , Trofoblastos/fisiología , Animales , Cadherinas/metabolismo , Trompas Uterinas/patología , Femenino , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Embarazo , Embarazo Tubario/patología , Remodelación Vascular , Vimentina/metabolismo , beta Catenina/metabolismo , Proteínas Roundabout
7.
Ann Anat ; 200: 79-87, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25819501

RESUMEN

Many human disorders induce high salinity in tissues and organs, interfering with their normal physiological functions. Using a mouse model, we demonstrated that high salt intake caused infertility. Specifically, we established that high salinity dramatically affects ovarian follicle development and the extent of follicular atresia. However, it did not significantly influence the primordial follicles. TUNEL assays revealed that high salt intake inhibited follicle development by inducing the granulosa and theca cells that surround the oocytes to undergo apoptosis. Furthermore, immunohistological staining for the proliferation markers Ki67 and PH3 showed that high salt intake also repressed granulosa cell proliferation. In vitro testing of granulosa cells also confirmed that high salt significantly repressed cell proliferation and promoted cell apoptosis. In summary, high salt consumption negatively impacts reproductive functions in female mice by interfering with ovarian folliculogenesis.


Asunto(s)
Folículo Ovárico/efectos de los fármacos , Folículo Ovárico/crecimiento & desarrollo , Cloruro de Sodio/toxicidad , Animales , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Femenino , Atresia Folicular/efectos de los fármacos , Células de la Granulosa/efectos de los fármacos , Etiquetado Corte-Fin in Situ , Infertilidad Femenina/inducido químicamente , Antígeno Ki-67/metabolismo , Ratones , Ratones Endogámicos C57BL , Oocitos/efectos de los fármacos , Embarazo , Cultivo Primario de Células , Células Tecales/efectos de los fármacos
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