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1.
Langmuir ; 35(23): 7459-7468, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-30379076

RESUMO

Collective migration is the mechanobiological interplay within migrating cell clusters and against extracellular matrixes (ECMs) underneath, mediating various physiological and pathological processes. Therefore, it is crucial to develop a robust platform on which collective migration can be studied under standardized conditions to understand how cells migrate differently between normal and disease states. We herein demonstrated phtotoactivatable hydrogel interfaces as suitable candidates for such applications. The substrate was composed of a poly(acrylamide) (PAAm) hydrogel whose surface was sequentially functionalized with poly-d-lysine (PDL) and photocleavable poly(ethylene glycol) (PEG). On the surface of the gel substrates, cell clusters with any given geometries can be prepared by controlling the irradiation patterns (geometrical cue), and their collective migration can be induced by the subsequent irradiation of the surrounding regions. Moreover, the substrate mechanical properties can be controlled by changing the composition of the PAAm hydrogel (mechanical cue), and the chemical properties were controlled by changing the amount of immobilized PDL, thereby altering the adsorbed amount of ECM proteins (chemical cue). The photoactivatable gel substrates were characterized by fluorescence microscopy, ζ-potential measurements, and the protein adsorption test. Through the study of the interplay of chemical, mechanical, and geometrical cues in the regulation of collective characteristics, we found additive effects of chemical and mechanical cues on the suppression of circular expansion by up-regulating the epithelial morphology. Also, the impact of geometrical cues became more significant by decreasing the chemical cue. We believe the present platform will be a useful research tool for the comprehensive mechanobiological analysis of collective cell migration.


Assuntos
Movimento Celular/efeitos dos fármacos , Hidrogéis/farmacologia , Luz , Fenômenos Mecânicos/efeitos dos fármacos , Animais , Fenômenos Biomecânicos/efeitos dos fármacos , Cães , Células Epiteliais/citologia , Células Madin Darby de Rim Canino , Polietilenoglicóis/química , Polietilenoglicóis/farmacologia
2.
Development ; 144(18): 3303-3314, 2017 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-28928282

RESUMO

Neuronal differentiation and cell-cycle exit are tightly coordinated, even in pathological situations. When pathological neurons re-enter the cell cycle and progress through the S phase, they undergo cell death instead of division. However, the mechanisms underlying mitotic resistance are mostly unknown. Here, we have found that acute inactivation of retinoblastoma (Rb) family proteins (Rb, p107 and p130) in mouse postmitotic neurons leads to cell death after S-phase progression. Checkpoint kinase 1 (Chk1) pathway activation during the S phase prevented the cell death, and allowed the division of cortical neurons that had undergone acute Rb family inactivation, oxygen-glucose deprivation (OGD) or in vivo hypoxia-ischemia. During neurogenesis, cortical neurons became protected from S-phase Chk1 pathway activation by the DNA methyltransferase Dnmt1, and underwent cell death after S-phase progression. Our results indicate that Chk1 pathway activation overrides mitotic safeguards and uncouples neuronal differentiation from mitotic resistance.


Assuntos
Divisão Celular , Quinase 1 do Ponto de Checagem/metabolismo , DNA (Citosina-5-)-Metiltransferases/metabolismo , Neurônios/citologia , Neurônios/enzimologia , Animais , Morte Celular , Hipóxia Celular , Sobrevivência Celular , DNA (Citosina-5-)-Metiltransferase 1 , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Glucose/deficiência , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/metabolismo , Neurogênese , Oxigênio , Proteína do Retinoblastoma/metabolismo , Fase S , Transdução de Sinais , Acidente Vascular Cerebral/patologia
3.
Adv Healthc Mater ; 6(11)2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28488337

RESUMO

Ischemic brain stroke is caused by blood flow interruption, leading to focal ischemia, neuron death, and motor, sensory, and/or cognitive dysfunctions. Angiogenesis, neovascularization from existing blood vessel, is essential for tissue growth and repair. Proangiogenic therapy for stroke is promising for preventing excess neuron death and improving functional recovery. Vascular endothelial growth factor (VEGF) is a critical factor for angiogenesis by promoting the proliferation, the survival, and the migration of endothelial cells. Here, angiogenic biomaterials to support injured brain regeneration are developed. Porous laminin (LN)-rich sponge (LN-sponge), on which histidine-tagged VEGF (VEGF-Histag) is immobilized via affinity interaction is developed. In an in vivo mouse stroke model, transplanting VEGF-Histag-LN-sponge produces remarkably stronger angiogenic activity than transplanting LN-sponge with soluble VEGF. The findings indicate that using affinity interactions to immobilize VEGF is a practical approach for developing angiogenic biomaterials for regenerating the injured brain.


Assuntos
Isquemia Encefálica , Proteínas Imobilizadas , Laminina , Neovascularização Fisiológica/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular , Animais , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Isquemia Encefálica/fisiopatologia , Modelos Animais de Doenças , Implantes de Medicamento/química , Implantes de Medicamento/farmacologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Proteínas Imobilizadas/química , Proteínas Imobilizadas/farmacologia , Laminina/química , Laminina/farmacologia , Camundongos , Porosidade , Fator A de Crescimento do Endotélio Vascular/farmacologia
4.
Tissue Eng Part A ; 21(1-2): 193-201, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25010638

RESUMO

After brain injury, neuroblasts generated from endogenous neural stem cells migrate toward the injured site using blood vessels as a scaffold, raising the possibility of reconstructing blood vessel network scaffolds as a strategy for promoting endogenous neuronal regeneration. In this study, we designed biomaterials based on the components and morphology of blood vessel scaffolds, and examined their ability to guide the migration of neuroblasts into a brain lesion site in mice. Transplanted porous sponge containing components of the basement membrane (BM) matrix enhanced neuroblast migration into the lesion, and detailed morphological examination suggested that the infiltrating cells used the BM sponge as a migration scaffold. Laminin (LN)-rich porous sponge also enhanced the migration of neuroblasts into the lesion, whereas BM gel and gelatin porous sponge did not. We conclude that the transplantation of LN-rich porous sponge promotes neuroblast migration into cortical lesions. This study highlights the possibility of using artificial blood vessel scaffolds to promote the regeneration of injured cerebral cortex.


Assuntos
Movimento Celular/efeitos dos fármacos , Córtex Cerebral/patologia , Laminina/farmacologia , Neurônios/citologia , Alicerces Teciduais/química , Animais , Astrócitos/citologia , Astrócitos/efeitos dos fármacos , Membrana Basal/química , Camundongos Endogâmicos ICR , Microglia/citologia , Microglia/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Poríferos , Porosidade
5.
Development ; 140(11): 2310-20, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23615279

RESUMO

Cell cycle dysregulation leads to abnormal proliferation and cell death in a context-specific manner. Cell cycle progression driven via the Rb pathway forces neurons to undergo S-phase, resulting in cell death associated with the progression of neuronal degeneration. Nevertheless, some Rb- and Rb family (Rb, p107 and p130)-deficient differentiating neurons can proliferate and form tumors. Here, we found in mouse that differentiating cerebral cortical excitatory neurons underwent S-phase progression but not cell division after acute Rb family inactivation in differentiating neurons. However, the differentiating neurons underwent cell division and proliferated when Rb family members were inactivated in cortical progenitors. Differentiating neurons generated from Rb(-/-); p107(-/-); p130(-/-) (Rb-TKO) progenitors, but not acutely inactivated Rb-TKO differentiating neurons, activated the DNA double-strand break (DSB) repair pathway without increasing trimethylation at lysine 20 of histone H4 (H4K20), which has a role in protection against DNA damage. The activation of the DSB repair pathway was essential for the cell division of Rb-TKO differentiating neurons. These results suggest that newly born cortical neurons from progenitors become epigenetically protected from DNA damage and cell division in an Rb family-dependent manner.


Assuntos
Córtex Cerebral/metabolismo , Neurogênese/fisiologia , Neurônios/metabolismo , Proteína do Retinoblastoma/metabolismo , Animais , Ciclo Celular , Diferenciação Celular , Proliferação de Células , Córtex Cerebral/embriologia , Dano ao DNA , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Histonas/metabolismo , Camundongos , Camundongos Knockout , Reparo de DNA por Recombinação , Proteína do Retinoblastoma/genética , Proteína p107 Retinoblastoma-Like/genética , Proteína p107 Retinoblastoma-Like/metabolismo , Proteína p130 Retinoblastoma-Like/genética , Proteína p130 Retinoblastoma-Like/metabolismo
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