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1.
Int J Nanomedicine ; 15: 7775-7789, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33116500

RESUMO

Purpose: Several scaffolds and cell sources are being investigated for cartilage regeneration. The aim of the study was to prepare nanocellulose-based thermosensitive injectable hydrogel scaffolds and assess their potential as 3D scaffolds allowing the chondrogenic differentiation of embedded human dental pulp stem and progenitor cells (hDPSCs). Materials and Methods: The hydrogel-forming solutions were prepared by adding ß-glycerophosphate (GP) to chitosan (CS) at different ratios. Nanocellulose (NC) suspension was produced from hemp hurd then added dropwise to the CS/GP mixture. In vitro characterization of the prepared hydrogels involved optimizing gelation and degradation time, mass-swelling ratio, and rheological properties. The hydrogel with optimal characteristics, NC-CS/GP-21, was selected for further investigation including assessment of biocompatibility. The chondrogenesis ability of hDPSCs embedded in NC-CS/GP-21 hydrogel was investigated in vitro and compared to that of bone marrow-derived mesenchymal stem cells (BMSCs), then was confirmed in vivo in 12 adult Sprague Dawley rats. Results: The selected hydrogel showed stability in culture media, had a gelation time of 2.8 minutes, showed a highly porous microstructure by scanning electron microscope, and was morphologically intact in vivo for 14 days after injection. Histological and immunohistochemical analyses and real-time PCR confirmed the chondrogenesis ability of hDPSCs embedded in NC-CS/GP-21 hydrogel. Conclusion: Our results suggest that nanocellulose-chitosan thermosensitive hydrogel is a biocompatible, injectable, mechanically stable and slowly degradable scaffold. hDPSCs embedded in NC-CS/GP-21 hydrogel is a promising, minimally invasive, stem cell-based strategy for cartilage regeneration.


Assuntos
Cartilagem/fisiologia , Diferenciação Celular/efeitos dos fármacos , Condrogênese/efeitos dos fármacos , Polpa Dentária/citologia , Hidrogéis/farmacologia , Regeneração/efeitos dos fármacos , Células-Tronco/citologia , Animais , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Cartilagem/citologia , Cartilagem/efeitos dos fármacos , Celulose/química , Quitosana/química , Humanos , Hidrogéis/química , Porosidade , Ratos , Ratos Sprague-Dawley , Células-Tronco/efeitos dos fármacos , Tecidos Suporte/química
2.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 36(8): 712-718, 2020 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-32958128

RESUMO

Objective To investigate the effect of Yiqihuoxue herb Naoluoxintong on cerebral vascular regeneration in rats of middle cerebral artery occlusion-reperfusion(MCAO-R)experimental model with Qi deficiency and blood stasis syndrome, and explore the possible mechanisms. Methods A total of 60 SD rats were randomly divided into a control group, a model group and three Naoluoxintong-treated groups [(1 200, 800 and 400 mg/(kg.d)], with 12 rats each. Except for the control group, the other groups were treated with modified suture method combined with multi-factor compound simulation to establish the models with both MCAO-R and syndrome of Qi deficiency accompanied by blood stasis. Neural functional deficit, blood stasis syndrome and Qi deficiency syndrome were scored by quantitative criteria for biological characteristics score. The regional cerebral blood flow (rCBF) was dynamically monitored with laser Doppler scanning. HE staining was used to observe the pathological changes of brain tissue. The mRNA expression levels of Wnt5a, glycogen synthase kinase-3ß (GSK-3ß) were determined by real-time fluorescent quantitative PCR, and the protein expression levels of ß-catenin, vascular endothelial growth factor (VEGF), AngII in the rat brain tissue were detected by Western blotting. Results Naoluoxintong improved neural functional in the model rats, reduced the scores of neural functional deficit, blood stasis syndrome and Qi deficiency syndrome, and restored rCBF simultaneously. Meanwhile, Naoluoxintong high- and middle-dose groups were better than any other model groups in terms of pathological changes, and the up-regulation of Wnt5a mRNA expression in these two groups was the most obvious. However, it had no significant effect on GSK3ß mRNA in the model rats. Expression levels of ß-catenin, VEGF, AngII protein were obviously up-regulated in Naoluoxintong high- and middle-dose groups. Conclusion Naoluoxintong can improve the rCBF with the aid of promoting cerebral vascular regeneration, which might be related to high expression of pro-angiogenic factors that are affected by Wnt signal path activation.


Assuntos
Vasos Sanguíneos , Isquemia Encefálica , Encéfalo , Qi , Animais , Vasos Sanguíneos/efeitos dos fármacos , Encéfalo/irrigação sanguínea , Encéfalo/fisiologia , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/genética , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/genética , Ratos , Ratos Sprague-Dawley , Regeneração/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/genética
3.
Bone Joint J ; 102-B(8): 1095-1106, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32731821

RESUMO

AIMS: Achilles tendon injuries are a frequent problem in orthopaedic surgery due to their limited healing capacity and the controversy surrounding surgical treatment. In recent years, tissue engineering research has focused on the development of biomaterials to improve this healing process. The aim of this study was to analyze the effect of tendon augmentation with a nanostructured fibrin-agarose hydrogel (NFAH) or genipin cross-linked nanostructured fibrin-agarose hydrogel (GP-NFAH), on the healing process of the Achilles tendon in rats. METHODS: NFAH, GP-NFAH, and MatriDerm (control) scaffolds were generated (five in each group). A biomechanical and cell-biomaterial-interaction characterization of these biomaterials was then performed: Live/Dead Cell Viability Assay, water-soluble tetrazolium salt-1 (WST-1) assay, and DNA-released after 48 hours. Additionally, a complete section of the left Achilles tendon was made in 24 Wistar rats. Animals were separated into four treatment groups (six in each group): direct repair (Control), tendon repair with MatriDerm, or NFAH, or GP-NFAH. Animals were euthanized for further histological analyses after four or eight weeks post-surgery. The Achilles tendons were harvested and a histopathological analysis was performed. RESULTS: Tensile test revealed that NFAH and GP-NFAH had significantly higher overall biomechanical properties compared with MatriDerm. Moreover, biological studies confirmed a high cell viability in all biomaterials, especially in NFAH. In addition, in vivo evaluation of repaired tendons using biomaterials (NFAH, GP-NFAH, and MatriDerm) resulted in better organization of the collagen fibres and cell alignment without clinical complications than direct repair, with a better histological score in GP-NFAH. CONCLUSION: In this animal model we demonstrated that NFAH and GP-NFAH had the potential to improve tendon healing following a surgical repair. However, future studies are needed to determine the clinical usefulness of these engineered strategies. Cite this article: Bone Joint J 2020;102-B(8):1095-1106.


Assuntos
Tendão do Calcâneo/cirurgia , Microambiente Celular/efeitos dos fármacos , Colágeno/uso terapêutico , Elastina/uso terapêutico , Regeneração/efeitos dos fármacos , Traumatismos dos Tendões/cirurgia , Tendão do Calcâneo/lesões , Animais , Materiais Biocompatíveis/farmacologia , Modelos Animais de Doenças , Fibrina/farmacologia , Hidrogéis/farmacologia , Masculino , Nanoestruturas , Distribuição Aleatória , Ratos , Ratos Wistar , Tendões/fisiologia , Engenharia Tecidual/métodos , Cicatrização/efeitos dos fármacos , Cicatrização/fisiologia
4.
PLoS One ; 15(7): e0236050, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32678832

RESUMO

Neurotrophic factors have been regarded having promising potentials for neuronal protection and regeneration, and thus promoting beneficial effects of kinesiological functions. They can be suspected to play important roles in cell/tissue grafting for various neural diseases. The clinical applications of such trophic factors to the central nervous system (CNS), however, have caused problematic side effects on account of the distinctive bioactive properties. In the course of developing synthetic compounds reflecting beneficial properties of basic fibroblast growth factor (bFGF), we conducted screening candidates that stimulate to trigger the intracellular tyrosine phosphorylation of FGF receptor and lead to the subsequent intracellular signaling in neurons. A small synthetic molecule SUN13837 was characterized by mimicking the beneficial properties of bFGF, which have been known as its specific activities when applied to CNS. What is more remarkable is that SUN13837 is eliminated the bioactivity to induce cell proliferation of non-neuronal somatic cells. On the bases of studies of pharmacology, behavior, physiology and histology, the present study reports that SUN13837 is characterized as a promising synthetic compound for treatment of devastating damages onto the rat spinal cord.


Assuntos
Materiais Biomiméticos/farmacologia , Fator 2 de Crescimento de Fibroblastos/metabolismo , Recuperação de Função Fisiológica/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Traumatismos da Medula Espinal/fisiopatologia , Animais , Axônios/efeitos dos fármacos , Axônios/fisiologia , Feminino , Crescimento Neuronal/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Regeneração/efeitos dos fármacos , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia
5.
Metabolism ; 111: 154324, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32712220

RESUMO

BACKGROUND: Clinical trials and animal studies have shown that sodium-glucose co-transporter type 2 (SGLT2) inhibitors improve pancreatic beta cell function. Our study aimed to investigate the effect of dapagliflozin on islet morphology and cell phenotype, and explore the origin and possible reason of the regenerated beta cells. METHODS: Two diabetic mouse models, db/db mice and pancreatic alpha cell lineage-tracing (glucagon-ß-gal) mice whose diabetes was induced by high fat diet combined with streptozotocin, were used. Mice were treated by daily intragastric administration of dapagliflozin (1 mg/kg) or vehicle for 6 weeks. The plasma insulin, glucagon and glucagon-like peptide-1 (GLP-1) were determined by using ELISA. The evaluation of islet morphology and cell phenotype was performed with immunofluorescence. Primary rodent islets and αTC1.9, a mouse alpha cell line, were incubated with dapagliflozin (0.25-25 µmol/L) or vehicle in the presence or absence of GLP-1 receptor antagonist for 24 h in regular or high glucose medium. The expression of specific markers and hormone levels were determined. RESULTS: Treatment with dapagliflozin significantly decreased blood glucose in the two diabetic models and upregulated plasma insulin and GLP-1 levels in db/db mice. The dapagliflozin treatment increased islet and beta cell numbers in the two diabetic mice. The beta cell proliferation as indicated by C-peptide and BrdU double-positive cells was boosted by dapagliflozin. The alpha to beta cell conversion, as evaluated by glucagon and insulin double-positive cells and confirmed by using alpha cell lineage-tracing, was facilitated by dapagliflozin. After the dapagliflozin treatment, some insulin-positive cells were located in the duct compartment or even co-localized with duct cell markers, suggestive of duct-derived beta cell neogenesis. In cultured primary rodent islets and αTC1.9 cells, dapagliflozin upregulated the expression of pancreatic endocrine progenitor and beta cell specific markers (including Pdx1) under high glucose condition. Moreover, dapagliflozin upregulated the expression of Pcsk1 (which encodes prohormone convertase 1/3, an important enzyme for processing proglucagon to GLP-1), and increased GLP-1 content and secretion in αTC1.9 cells. Importantly, the dapagliflozin-induced upregulation of Pdx1 expression was attenuated by GLP-1 receptor antagonist. CONCLUSIONS: Except for glucose-lowering effect, dapagliflozin has extra protective effects on beta cells in type 2 diabetes. Dapagliflozin enhances beta cell self-replication, induces alpha to beta cell conversion, and promotes duct-derived beta cell neogenesis. The promoting effects of dapagliflozin on beta cell regeneration may be partially mediated via GLP-1 secreted from alpha cells.


Assuntos
Compostos Benzidrílicos/farmacologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Células Endócrinas/efeitos dos fármacos , Células Secretoras de Glucagon/efeitos dos fármacos , Glucosídeos/farmacologia , Regeneração/efeitos dos fármacos , Animais , Glicemia/metabolismo , Peptídeo C/metabolismo , Modelos Animais de Doenças , Células Endócrinas/metabolismo , Glucagon/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Células Secretoras de Glucagon/metabolismo , Glucose/metabolismo , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Masculino , Camundongos , Pró-Proteína Convertase 1/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose
6.
Jt Dis Relat Surg ; 31(2): 260-266, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32584723

RESUMO

OBJECTIVES: This study aims to investigate the effects of hyperbaric oxygen (HBO) therapy and platelet-rich plasma (PRP) on the regeneration of osteochondral defects of the rats, and the synergistic effect of this combined treatment. MATERIALS AND METHODS: This randomized, controlled, and interventional animal study was conducted between May 2014 and August 2014 Osteochondral regeneration was evaluated in four treatment groups (control, PRP, HBO, and HBO+PRP groups) at the 30th day after iatrogenic injury. Thirty-two female Wistar albino rats (weighing 248-305 g) underwent arthrotomy and osteochondral surgery on left knees. The regenerations of defects were then examined histologically by the modified version of O'Driscoll score. RESULTS: Groups that were treated with either HBO or PRP alone regenerated significantly better than the control group (p=0.01), while no significant difference was found between the HBO- and PRP-treated groups (p>0.05). The defects in group 4 (treated with both HBO and PRP) regenerated significantly better than the control group, the HBO-treated group alone, and the PRP-treated group alone (p=0.01). CONCLUSION: The results of this study showed a synergistic effect of HBO and PRP on knee cartilage regeneration. However, the possible underlying mechanisms should be the subject of future researches. The aggregation and activation of growth factors released from platelets whose activation is increased in the hyperbaric environment may explain this effect. This may result in a better regeneration than the effect of PRP or HBO alone.


Assuntos
Cartilagem , Oxigenação Hiperbárica/métodos , Articulação do Joelho/cirurgia , Plasma Rico em Plaquetas/metabolismo , Regeneração/efeitos dos fármacos , Animais , Cartilagem/efeitos dos fármacos , Cartilagem/lesões , Cartilagem/fisiologia , Terapia Combinada/métodos , Modelos Anatômicos , Ratos , Ratos Wistar , Resultado do Tratamento , Cicatrização/efeitos dos fármacos
7.
Proc Natl Acad Sci U S A ; 117(26): 15322-15331, 2020 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-32541049

RESUMO

Wound healing in plant tissues, consisting of rigid cell wall-encapsulated cells, represents a considerable challenge and occurs through largely unknown mechanisms distinct from those in animals. Owing to their inability to migrate, plant cells rely on targeted cell division and expansion to regenerate wounds. Strict coordination of these wound-induced responses is essential to ensure efficient, spatially restricted wound healing. Single-cell tracking by live imaging allowed us to gain mechanistic insight into the wound perception and coordination of wound responses after laser-based wounding in Arabidopsis root. We revealed a crucial contribution of the collapse of damaged cells in wound perception and detected an auxin increase specific to cells immediately adjacent to the wound. This localized auxin increase balances wound-induced cell expansion and restorative division rates in a dose-dependent manner, leading to tumorous overproliferation when the canonical TIR1 auxin signaling is disrupted. Auxin and wound-induced turgor pressure changes together also spatially define the activation of key components of regeneration, such as the transcription regulator ERF115. Our observations suggest that the wound signaling involves the sensing of collapse of damaged cells and a local auxin signaling activation to coordinate the downstream transcriptional responses in the immediate wound vicinity.


Assuntos
Arabidopsis/fisiologia , Ácidos Indolacéticos/metabolismo , Células Vegetais/fisiologia , Raízes de Plantas/fisiologia , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Divisão Celular , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Ácidos Indolacéticos/antagonistas & inibidores , Cinurenina/farmacologia , Lasers , Ftalimidas/farmacologia , Células Vegetais/efeitos dos fármacos , Regeneração/efeitos dos fármacos , Regeneração/fisiologia , Transdução de Sinais/fisiologia , Triazóis/farmacologia
8.
PLoS One ; 15(6): e0234650, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32555733

RESUMO

To investigate auricular reconstruction by tissue engineering means, this study compared cartilage regenerated from human chondrocytes obtained from either microtia or normal (conchal) tissues discarded from otoplasties. Isolated cells were expanded in vitro, seeded onto nanopolyglycolic acid (nanoPGA) sheets with or without addition of bone morphogenetic protein-7 (BMP7), and implanted in nude mice for 10 weeks. On specimen harvest, cartilage development was assessed by gross morphology, histology, and RT-qPCR and microarray analyses. Neocartilages from normal and microtia surgical tissues were found equivalent in their dimensions, qualitative degree of proteoglycan and elastic fiber staining, and quantitative gene expression levels of types II and III collagen, elastin, and SOX5. Microarray analysis, applied for the first time for normal and microtia neocartilage comparison, yielded no genes that were statistically significantly different in expression between these two sample groups. These results support use of microtia tissue as a cell source for normal auricular reconstruction. Comparison of normal and microtia cells, each seeded on nanoPGA and supplemented with BMP7 in a slow-release hydrogel, showed statistically significant differences in certain genes identified by microarray analysis. Such differences were also noted in several analyses comparing counterpart seeded cells without BMP7. Summary data suggest a possible application for BMP7 in microtia cartilage regeneration and encourage further studies to elucidate whether such genotypic differences translate to phenotypic characteristics of the human microtic ear. The present work advances understanding relevant to the potential clinical use of microtia surgical remnants as a suitable cell source for tissue engineering of the pinna.


Assuntos
Proteína Morfogenética Óssea 7/farmacologia , Microtia Congênita/cirurgia , Cartilagem da Orelha/patologia , Procedimentos Cirúrgicos Reconstrutivos , Regeneração , Adolescente , Animais , Criança , Pré-Escolar , Microtia Congênita/genética , Cartilagem da Orelha/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos Nus , Regeneração/efeitos dos fármacos , Engenharia Tecidual
9.
J Plast Reconstr Aesthet Surg ; 73(9): 1738-1746, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32418841

RESUMO

INTRODUCTION: Diabetes mellitus remains a significant public health problem, consuming over $400 billion every year. While Diabetes itself can be controlled effectively, impaired wound healing still occurs frequently in diabetic patients. Adipose-derived mesenchymal stem cells (ASCs) provide an especially appealing source for diabetic wound cell therapy. With autologous approaches, the functionality of ASCs largely underlie patient-dependent factors. Diabetes is a significant diminishing factor of MSC functionality. Here, we explore a novel strategy to enhance diabetic ASC functionality through deferoxamine (DFO) preconditioning. MATERIAL AND METHODS: Human diabetic ASCs have been preconditioned with 150 µM and 300 µM DFO in vitro and analyzed for regenerative cytokine expression. Murine diabetic ASCs have been preconditioned with 150 µM DFO examined for their in vitro and in vivo vasculogenic capacity in Matrigel assays. Additionally, a diabetic murine wound healing model has been performed to assess the regenerative capacity of preconditioned cells. RESULTS: DFO preconditioning enhances the VEGF expression of human diabetic ASCs through hypoxia-inducible factor upregulation. The use of 150 µM of DFO was an optimal concentration to induce regenerative effects. The vasculogenic potential of preconditioned diabetic ASCs is significantly greater in vitro and in vivo. The enhanced regenerative functionality of DFO preconditioned ASCs was further confirmed in a model of diabetic murine wound healing. CONCLUSION: These results demonstrate that DFO significantly induced the upregulation of hypoxia-inducible factor-1 alpha and VEGF in diabetic ASCs and showed efficacy in the treatment of diabetes-associated deficits of wound healing. The favorable status of DFO as a small molecule drug approved since decades for multiple indications makes this approach highly translatable.


Assuntos
Desferroxamina/farmacologia , Diabetes Mellitus Experimental/metabolismo , Células-Tronco Mesenquimais/metabolismo , Regeneração/efeitos dos fármacos , Adulto , Idoso , Animais , Células Cultivadas , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Camundongos , Pessoa de Meia-Idade , Neovascularização Fisiológica/efeitos dos fármacos , Regulação para Cima , Fator A de Crescimento do Endotélio Vascular/metabolismo , Cicatrização/efeitos dos fármacos
10.
PLoS One ; 15(5): e0232981, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32396580

RESUMO

Cell signaling pathways play key roles in coordinating cellular events in development. The Notch signaling pathway is highly conserved across all multicellular animals and is known to coordinate a multitude of diverse cellular events, including proliferation, differentiation, fate specification, and cell death. Specific functions of the pathway are, however, highly context-dependent and are not well characterized in post-traumatic regeneration. Here, we use a small-molecule inhibitor of the pathway (DAPT) to demonstrate that Notch signaling is required for proper arm regeneration in the brittle star Ophioderma brevispina, a highly regenerative member of the phylum Echinodermata. We also employ a transcriptome-wide gene expression analysis (RNA-seq) to characterize the downstream genes controlled by the Notch pathway in the brittle star regeneration. We demonstrate that arm regeneration involves an extensive cross-talk between the Notch pathway and other cell signaling pathways. In the regrowing arm, Notch regulates the composition of the extracellular matrix, cell migration, proliferation, and apoptosis, as well as components of the innate immune response. We also show for the first time that Notch signaling regulates the activity of several transposable elements. Our data also suggests that one of the possible mechanisms through which Notch sustains its activity in the regenerating tissues is via suppression of Neuralized1.


Assuntos
Equinodermos/fisiologia , Receptores Notch/fisiologia , Regeneração/fisiologia , Estruturas Animais/efeitos dos fármacos , Estruturas Animais/fisiologia , Animais , Elementos de DNA Transponíveis , Dipeptídeos/farmacologia , Regulação para Baixo/efeitos dos fármacos , Equinodermos/efeitos dos fármacos , Equinodermos/genética , Receptores Notch/antagonistas & inibidores , Receptores Notch/genética , Regeneração/efeitos dos fármacos , Regeneração/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Transcriptoma/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
11.
Arterioscler Thromb Vasc Biol ; 40(7): 1627-1634, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32434408

RESUMO

Peripheral artery disease is a common disorder and a major cause of morbidity and mortality worldwide. Therapy is directed at reducing the risk of major adverse cardiovascular events and at ameliorating symptoms. Medical therapy is effective at reducing the incidence of myocardial infarction and stroke to which these patients are prone but is inadequate in relieving limb-related symptoms, such as intermittent claudication, rest pain, and ischemic ulceration. Limb-related morbidity is best addressed with surgical and endovascular interventions that restore perfusion. Current medical therapies have only modest effects on limb blood flow. Accordingly, there is an opportunity to develop medical approaches to restore limb perfusion. Vascular regeneration to enhance limb blood flow includes methods to enhance angiogenesis, arteriogenesis, and vasculogenesis using angiogenic cytokines and cell therapies. We review the molecular mechanisms of these processes; briefly discuss what we have learned from the clinical trials of angiogenic and cell therapies; and conclude with an overview of a potential new approach based upon transdifferentiation to enhance vascular regeneration in peripheral artery disease.


Assuntos
Indutores da Angiogênese/uso terapêutico , Artérias/efeitos dos fármacos , Citocinas/uso terapêutico , Neovascularização Fisiológica/efeitos dos fármacos , Doença Arterial Periférica/terapia , Regeneração/efeitos dos fármacos , Transplante de Células-Tronco , Animais , Artérias/metabolismo , Artérias/patologia , Artérias/fisiopatologia , Humanos , Doença Arterial Periférica/metabolismo , Doença Arterial Periférica/patologia , Doença Arterial Periférica/fisiopatologia , Recuperação de Função Fisiológica , Fluxo Sanguíneo Regional , Resultado do Tratamento
12.
PLoS One ; 15(4): e0230392, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32275672

RESUMO

OBJECTIVES: High-mobility group box 1 protein (HMGB1) fragment enhances bone marrow-derived mesenchymal stem cell (BM-MSC) recruitment to damaged tissue to promote tissue regeneration. This study aimed to evaluate whether systemic injection of HMGB1 fragment could promote tissue repair in a rat model of myocardial infarction (MI). METHODS: HMGB1 (n = 14) or phosphate buffered saline (n = 12, control) was administered to MI rats for 4 days. Cardiac performance and left ventricular remodeling were evaluated using ultrasonography and immunostaining. BM-MSC recruitment to damaged tissue in green fluorescent protein-bone marrow transplantation (GFP-BMT) models was evaluated using immunostaining. RESULTS: At four weeks post-treatment, the left ventricular ejection fraction was significantly improved in the HMGB1 group compared to that in the control. Interstitial fibrosis and cardiomyocyte hypertrophy were also significantly attenuated in the HMGB1 group compared to the control. In the peri-infarction area, VEGF-A mRNA expression was significantly higher and TGFß expression was significantly attenuated in the HMGB1 group than in the control. In GFP-BMT rats, GFP+/PDGFRα+ cells were significantly mobilized to the peri-infarction area in the HMGB1 group compared to that in the control, leading to the formation of new vasculature. In addition, intravital imaging revealed that more GFP+/PDGFRα+ cells were recruited to the peri-infarction area in the HMGB1 group than in the control 12 h after treatment. CONCLUSIONS: Systemic administration of HMGB1 induced angiogenesis and reduced fibrosis by recruiting PDGFRα+ mesenchymal cells from the bone marrow, suggesting that HMGB1 administration might be a new therapeutic approach for heart failure after MI.


Assuntos
Proteína HMGB1/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Infarto do Miocárdio/tratamento farmacológico , Indutores da Angiogênese/farmacologia , Animais , Modelos Animais de Doenças , Fibrose/tratamento farmacológico , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Coração/fisiopatologia , Insuficiência Cardíaca/tratamento farmacológico , Masculino , Células-Tronco Mesenquimais/metabolismo , Infarto do Miocárdio/fisiopatologia , Ratos , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Regeneração/efeitos dos fármacos
13.
Sci Adv ; 6(10): eaaz1094, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32181358

RESUMO

Mesenchymal stem cells (MSCs) encapsulation by three-dimensionally (3D) printed matrices were believed to provide a biomimetic microenvironment to drive differentiation into tissue-specific progeny, which made them a great therapeutic potential for regenerative medicine. Despite this potential, the underlying mechanisms of controlling cell fate in 3D microenvironments remained relatively unexplored. Here, we bioprinted a sweat gland (SG)-like matrix to direct the conversion of MSC into functional SGs and facilitated SGs recovery in mice. By extracellular matrix differential protein expression analysis, we identified that CTHRC1 was a critical biochemical regulator for SG specification. Our findings showed that Hmox1 could respond to the 3D structure activation and also be involved in MSC differentiation. Using inhibition and activation assay, CTHRC1 and Hmox1 synergistically boosted SG gene expression profile. Together, these findings indicated that biochemical and structural cues served as two critical impacts of 3D-printed matrix on MSC fate decision into the glandular lineage and functional SG recovery.


Assuntos
Queimaduras/terapia , Matriz Extracelular/metabolismo , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/metabolismo , Regeneração/efeitos dos fármacos , Glândulas Sudoríparas/metabolismo , Acetilcolina/farmacologia , Animais , Queimaduras/genética , Queimaduras/metabolismo , Queimaduras/patologia , Diferenciação Celular , Proliferação de Células , Células Imobilizadas , Matriz Extracelular/química , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Regulação da Expressão Gênica , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Membro Posterior/lesões , Membro Posterior/metabolismo , Hidrogéis , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Células-Tronco Mesenquimais/citologia , Camundongos , Camundongos Endogâmicos C57BL , Impressão Tridimensional , Regeneração/genética , Glândulas Sudoríparas/efeitos dos fármacos , Glândulas Sudoríparas/lesões , Tecidos Suporte
14.
Nat Commun ; 11(1): 1435, 2020 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-32188843

RESUMO

Regeneration of corneal stroma has always been a challenge due to its sophisticated structure and keratocyte-fibroblast transformation. In this study, we fabricate grid poly (ε-caprolactone)-poly (ethylene glycol) microfibrous scaffold and infuse the scaffold with gelatin methacrylate (GelMA) hydrogel to obtain a 3 D fiber hydrogel construct; the fiber spacing is adjusted to fabricate optimal construct that simulates the stromal structure with properties most similar to the native cornea. The topological structure (3 D fiber hydrogel, 3 D GelMA hydrogel, and 2 D culture dish) and chemical factors (serum, ascorbic acid, insulin, and ß-FGF) are examined to study their effects on the differentiation of limbal stromal stem cells to keratocytes or fibroblasts and the phenotype maintenance, in vitro and in vivo tissue regeneration. The results demonstrate that fiber hydrogel and serum-free media synergize to provide an optimal environment for the maintenance of keratocyte phenotype and the regeneration of damaged corneal stroma.


Assuntos
Substância Própria/fisiologia , Gelatina/farmacologia , Hidrogéis/farmacologia , Metacrilatos/farmacologia , Poliésteres/farmacologia , Polietilenoglicóis/farmacologia , Regeneração , Animais , Substância Própria/efeitos dos fármacos , Citoesqueleto/efeitos dos fármacos , Citoesqueleto/metabolismo , Limbo da Córnea/citologia , Masculino , Ratos Sprague-Dawley , Regeneração/efeitos dos fármacos , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos , Estresse Mecânico , Células Estromais/citologia , Células Estromais/efeitos dos fármacos , Suínos , Tecidos Suporte/química , Vimentina/metabolismo
15.
Nat Commun ; 11(1): 1571, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32218432

RESUMO

Estrogens and progesterone control breast development and carcinogenesis via their cognate receptors expressed in a subset of luminal cells in the mammary epithelium. How they control the extracellular matrix, important to breast physiology and tumorigenesis, remains unclear. Here we report that both hormones induce the secreted protease Adamts18 in myoepithelial cells by controlling Wnt4 expression with consequent paracrine canonical Wnt signaling activation. Adamts18 is required for stem cell activation, has multiple binding partners in the basement membrane and interacts genetically with the basal membrane-specific proteoglycan, Col18a1, pointing to the basement membrane as part of the stem cell niche. In vitro, ADAMTS18 cleaves fibronectin; in vivo, Adamts18 deletion causes increased collagen deposition during puberty, which results in impaired Hippo signaling and reduced Fgfr2 expression both of which control stem cell function. Thus, Adamts18 links luminal hormone receptor signaling to basement membrane remodeling and stem cell activation.


Assuntos
Proteínas ADAMTS/metabolismo , Hormônios/farmacologia , Glândulas Mamárias Animais/citologia , Nicho de Células-Tronco , Células-Tronco/metabolismo , Proteínas ADAMTS/deficiência , Proteínas ADAMTS/genética , Animais , Antígenos CD/metabolismo , Linhagem Celular , Autorrenovação Celular/efeitos dos fármacos , Epitélio/metabolismo , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Feminino , Fibronectinas/metabolismo , Glicoproteínas/metabolismo , Humanos , Camundongos Endogâmicos C57BL , Modelos Biológicos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Progesterona/metabolismo , Regeneração/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Nicho de Células-Tronco/efeitos dos fármacos , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos , Transcrição Genética/efeitos dos fármacos
16.
J Pharmacol Sci ; 143(2): 117-121, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32220570

RESUMO

There are several animal models of glucocorticoid-induced osteoporosis (GIOP), but each requires a long time to evaluate drug effects. Zebrafish scales are classified as dermal bone and potentially represent a convenient animal model of GIOP because they rapidly regenerate following their removal. We clarified that dexamethasone-treated regenerating scales showed malformations, decreased size and circularity. Anti-osteoporosis drugs rescued the scale malformation phenotype eight-days following the removal of scales. Hence, the dexamethasone-induced regenerating scale malformation model may be a useful animal model for discovering drugs to treat GIOP.


Assuntos
Escamas de Animais/patologia , Escamas de Animais/fisiologia , Conservadores da Densidade Óssea/uso terapêutico , Dexametasona/efeitos adversos , Modelos Animais de Doenças , Osteoporose/induzido quimicamente , Osteoporose/tratamento farmacológico , Regeneração , Animais , Conservadores da Densidade Óssea/farmacologia , Fenótipo , Regeneração/efeitos dos fármacos , Peixe-Zebra
17.
Genes Dev ; 34(7-8): 489-494, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32139422

RESUMO

Young mammals possess a limited regenerative capacity in some tissues, which is lost upon maturation. We investigated whether cellular senescence might play a role in such loss during liver regeneration. We found that following partial hepatectomy, the senescence-associated genes p21, p16Ink4a, and p19Arf become dynamically expressed in different cell types when regenerative capacity decreases, but without a full senescent response. However, we show that treatment with a senescence-inhibiting drug improves regeneration, by disrupting aberrantly prolonged p21 expression. This work suggests that senescence may initially develop from heterogeneous cellular responses, and that senotherapeutic drugs might be useful in promoting organ regeneration.


Assuntos
Compostos de Bifenilo/farmacologia , Inibidor de Quinase Dependente de Ciclina p21/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Fígado/fisiologia , Nitrofenóis/farmacologia , Regeneração/efeitos dos fármacos , Sulfonamidas/farmacologia , Animais , Células Cultivadas , Senescência Celular/efeitos dos fármacos , Inibidor p16 de Quinase Dependente de Ciclina/genética , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Piperazinas/farmacologia
18.
Int J Nanomedicine ; 15: 1721-1730, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32210562

RESUMO

Introduction: In this study, the combination of TEMPO-oxidized sacchachitin nanofibers (TOSCNFs) with chitosan-activated platelet-rich plasma (cPRP) was evaluated for remedying dry eye syndrome (DES). Methods: TOSCNFs, designated T050SC, were generated. T050SC combined with chitosan-activated (cPRP) was formulated as eye drops for application for severe DES. To evaluate the effects of cPRP and TOSCNFs on the repair of corneal injury, in vitro studies were conducted using Statens Seruminstitut rabbit corneal (SIRC) epithelial cells for cell proliferation and cell migration assays, and a severe DES animal model using rabbits was established with benzalkonium chloride (BAC) treatment for the evaluation. Results: Results showed that the optimal eye formulation contained PRP activated by 350 µg/mL of the low-molecular-weight chitosan group (L3) combined with 300 µg/mL TO50SC (L3+T050SC). In the WST-1 cell-proliferation assay, L3 and L3+TO50SC significantly increased Statens SIRC cell proliferation after 24 hrs of incubation. In the SIRC cell migration assay, the L3+TO50SC group showed a wound-healing efficiency of 89% after 24-hr treatment. After 5 days of treatment, Schirmer's test results did not simulate the dry eye animal model. Typical cornea appearance and eye fluorescein staining results showed that the L3 group had the best effect on improving cornea haze and epithelial damage. Conclusion: This study has determined that TOSCNFs effectively promoted the healing effect on severe cases of corneal damage, and also might enhance the clinical application and medical potential of PRP in ophthalmology.


Assuntos
Quitina/química , Óxidos N-Cíclicos/química , Síndromes do Olho Seco/terapia , Glucanos/química , Nanofibras/química , Plasma Rico em Plaquetas/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Quitina/farmacologia , Córnea/efeitos dos fármacos , Córnea/patologia , Córnea/cirurgia , Modelos Animais de Doenças , Síndromes do Olho Seco/patologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Fibroblastos/efeitos dos fármacos , Glucanos/farmacologia , Nanofibras/ultraestrutura , Oxirredução , Coelhos , Regeneração/efeitos dos fármacos
19.
Nat Rev Rheumatol ; 16(5): 255-267, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32203285

RESUMO

Lupus nephritis (LN) is a common manifestation of systemic lupus erythematosus that can lead to irreversible renal impairment. Although the prognosis of LN has improved substantially over the past 50 years, outcomes have plateaued in the USA in the past 20 years as immunosuppressive therapies have failed to reverse disease in more than half of treated patients. This failure might reflect disease complexity and heterogeneity, as well as social and economic barriers to health-care access that can delay intervention until after damage has already occurred. LN progression is still poorly understood and involves multiple cell types and both immune and non-immune mechanisms. Single-cell analysis of intrinsic renal cells and infiltrating cells from patients with LN is a new approach that will help to define the pathways of renal injury at a cellular level. Although many new immune-modulating therapies are being tested in the clinic, the development of therapies to improve regeneration of the injured kidney and to prevent fibrosis requires a better understanding of the mechanisms of LN progression. This mechanistic understanding, together with the development of clinical measures to evaluate risk and detect early disease and better access to expert health-care providers, should improve outcomes for patients with LN.


Assuntos
Rim/citologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/patologia , Nefrite Lúpica/complicações , Biomarcadores/análise , Ensaios Clínicos como Assunto , Progressão da Doença , Diagnóstico Precoce , Fibrose/prevenção & controle , Acesso aos Serviços de Saúde/estatística & dados numéricos , Humanos , Imunossupressores/uso terapêutico , Rim/lesões , Rim/metabolismo , Rim/patologia , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/prevenção & controle , Lúpus Eritematoso Sistêmico/epidemiologia , Nefrite Lúpica/genética , Nefrite Lúpica/imunologia , Prognóstico , Regeneração/efeitos dos fármacos , Regeneração/fisiologia , Fatores Socioeconômicos , Estados Unidos/epidemiologia
20.
Molecules ; 25(3)2020 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-32046280

RESUMO

Due to its properties, such as biodegradability, low density, excellent biocompatibility and unique mechanics, spider silk has been used as a natural biomaterial for a myriad of applications. First clinical applications of spider silk as suture material go back to the 18th century. Nowadays, since natural production using spiders is limited due to problems with farming spiders, recombinant production of spider silk proteins seems to be the best way to produce material in sufficient quantities. The availability of recombinantly produced spider silk proteins, as well as their good processability has opened the path towards modern biomedical applications. Here, we highlight the research on spider silk-based materials in the field of tissue engineering and summarize various two-dimensional (2D) and three-dimensional (3D) scaffolds made of spider silk. Finally, different applications of spider silk-based materials are reviewed in the field of tissue engineering in vitro and in vivo.


Assuntos
Materiais Biocompatíveis/química , Regeneração/efeitos dos fármacos , Seda/química , Aranhas/química , Engenharia Tecidual/métodos , Animais , Materiais Biocompatíveis/isolamento & purificação , Materiais Biocompatíveis/metabolismo , Materiais Biocompatíveis/farmacologia , Vasos Sanguíneos/citologia , Vasos Sanguíneos/efeitos dos fármacos , Osso e Ossos/citologia , Osso e Ossos/efeitos dos fármacos , Cartilagem/citologia , Cartilagem/efeitos dos fármacos , Técnicas de Cultura de Células , Humanos , Hidrogéis/química , Nervos Periféricos/citologia , Nervos Periféricos/efeitos dos fármacos , Proteínas Recombinantes/química , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacologia , Regeneração/fisiologia , Seda/biossíntese , Seda/isolamento & purificação , Seda/farmacologia , Pele/citologia , Pele/efeitos dos fármacos , Aranhas/fisiologia , Substâncias Viscoelásticas/química
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