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1.
Nat Biomed Eng ; 5(8): 880-896, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34426676

RESUMO

Fibroblasts can be directly reprogrammed into cardiomyocytes, endothelial cells or smooth muscle cells. Here we report the reprogramming of mouse tail-tip fibroblasts simultaneously into cells resembling these three cell types using the microRNA mimic miR-208b-3p, ascorbic acid and bone morphogenetic protein 4, as well as the formation of tissue-like structures formed by the directly reprogrammed cells. Implantation of the formed cardiovascular tissue into the infarcted hearts of mice led to the migration of reprogrammed cells to the injured tissue, reducing regional cardiac strain and improving cardiac function. The migrated endothelial cells and smooth muscle cells contributed to vessel formation, and the migrated cardiomyocytes, which initially displayed immature characteristics, became mature over time and formed gap junctions with host cardiomyocytes. Direct reprogramming of somatic cells to make cardiac tissue may aid the development of applications in cell therapy, disease modelling and drug discovery for cardiovascular diseases.


Assuntos
Células Endoteliais/transplante , Coração/fisiologia , Infarto do Miocárdio/terapia , Miócitos de Músculo Liso/transplante , Regeneração , Animais , Ácido Ascórbico/farmacologia , Proteína Morfogenética Óssea 4/farmacologia , Reprogramação Celular/efeitos dos fármacos , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Fibroblastos/citologia , Fibroblastos/metabolismo , Junções Comunicantes/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Miocárdio/citologia , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/metabolismo , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo , Neovascularização Fisiológica , Transcriptoma
2.
Sci Rep ; 11(1): 3630, 2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33574435

RESUMO

Preeclampsia (PE) is a prevalent pregnancy disorder that leads to high maternal and fetal morbidity and mortality. While defective vascular development and angiogenesis in placenta are known as crucial pathological findings, its pathophysiological mechanism remains elusive. To better understand the effects of PE on angio-vasculogenesis and inflammatory networks in the fetus and to identify their biological signatures, we investigated the quantitative and functional characteristics of cord blood-derived mononuclear cells (CB-MNCs) and CD31-positive MNCs. Flow cytometry analysis demonstrated that the CB-MNCs from the severe PE group had significantly decreased number of cells expressing CD3, CD11b, CD14, CD19, KDR, and CD31 compared with the normal group. Quantitative real time PCR (qRT-PCR) shows down-regulation of the major angiogenic factor VEGFA in MNCs and CD31+ MNCs in severe PE. The major inflammatory cytokines IL1 was highly upregulated in CD31+ CB-MNCs in the severe PE patients. Mild PE patients, however, did not display any significant difference in expression of all measured angiogenic genes and most inflammatory genes. These findings show distinct angiogenic and inflammatory signatures from severe PE, and they may play a significant role in the pathogenesis of vascular defects in placenta of severe PE.

3.
Adv Drug Deliv Rev ; 170: 142-199, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33428994

RESUMO

Atherosclerosis is a chronic inflammatory disease driven by lipid accumulation in arteries, leading to narrowing and thrombosis. It affects the heart, brain, and peripheral vessels and is the leading cause of mortality in the United States. Researchers have strived to design nanomaterials of various functions, ranging from non-invasive imaging contrast agents, targeted therapeutic delivery systems to multifunctional nanoagents able to target, diagnose, and treat atherosclerosis. Therefore, this review aims to summarize recent progress (2017-now) in the development of nanomaterials and their applications to improve atherosclerosis diagnosis and therapy during the preclinical and clinical stages of the disease.


Assuntos
Aterosclerose , Nanoestruturas , Animais , Aterosclerose/diagnóstico , Aterosclerose/tratamento farmacológico , Humanos , Nanoestruturas/química , Nanoestruturas/uso terapêutico
4.
Sci Rep ; 10(1): 8061, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32415167

RESUMO

CBX7 is a polycomb group protein, and despite being implicated in many diseases, its role in cell proliferation has been controversial: some groups described its pro-proliferative properties, but others illustrated its inhibitory effects on cell growth. To date, the reason for the divergent observations remains unknown. While several isoforms for CBX7 were reported, no studies investigated whether the divergent roles of CBX7 could be due to distinct functions of CBX7 isoforms. In this study, we newly identified mouse CBX7 transcript variant 1 (mCbx7v1), which is homologous to the human CBX7 gene (hCBX7v1) and is expressed in various mouse organs. We revealed that mCbx7v1 and hCBX7v1 encode a 36 kDa protein (p36CBX7) whereas mCbx7 and hCBX7v3 encode a 22 kDa protein (p22CBX7). This study further demonstrated that p36CBX7 was localized to the nucleus and endogenously expressed in proliferating cells whereas p22CBX7 was localized to the cytoplasm, induced by serum starvation in both human and mouse cells, and inhibited cell proliferation. Together, these data indicate that CBX7 isoforms are localized in different locations in a cell and play differing roles in cell proliferation. This varying function of CBX7 isoforms may help us understand the distinct function of CBX7 in various studies.


Assuntos
Regulação da Expressão Gênica , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 1/metabolismo , Sequência de Aminoácidos , Animais , Biomarcadores , Proliferação de Células , Imunofluorescência , Humanos , Espaço Intracelular/metabolismo , Camundongos , Complexo Repressor Polycomb 1/química , Isoformas de Proteínas , Transporte Proteico
5.
Circ Res ; 125(12): 1141-1145, 2019 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-31804914

RESUMO

Cardiovascular diseases have shown a continuous increase in Korea over the past decade and became the second most common cause of mortality in Korea. Although the number and the amount of total grants for cardiovascular research have increased in Korea, the proportion of the number of grants and total amount allocated for the cardiac/cardiovascular field to all health and medical research fields has not changed much over this period. In addition, the publications related to clinical research have substantially increased in Korea along with the number of nation-wide registries for cardiovascular diseases, but basic and translational research did not show significant growth, requiring new measures to promote basic and translational cardiovascular research in Korea.


Assuntos
Pesquisa Biomédica/tendências , Doenças Cardiovasculares/epidemiologia , Publicações Periódicas como Assunto/tendências , Sistema de Registros , Sociedades Médicas/tendências , Pesquisa Biomédica/métodos , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/terapia , Humanos , República da Coreia/epidemiologia
6.
Nat Methods ; 16(11): 1169-1175, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31591580

RESUMO

Human cortical organoids (hCOs), derived from human embryonic stem cells (hESCs), provide a platform to study human brain development and diseases in complex three-dimensional tissue. However, current hCOs lack microvasculature, resulting in limited oxygen and nutrient delivery to the inner-most parts of hCOs. We engineered hESCs to ectopically express human ETS variant 2 (ETV2). ETV2-expressing cells in hCOs contributed to forming a complex vascular-like network in hCOs. Importantly, the presence of vasculature-like structures resulted in enhanced functional maturation of organoids. We found that vascularized hCOs (vhCOs) acquired several blood-brain barrier characteristics, including an increase in the expression of tight junctions, nutrient transporters and trans-endothelial electrical resistance. Finally, ETV2-induced endothelium supported the formation of perfused blood vessels in vivo. These vhCOs form vasculature-like structures that resemble the vasculature in early prenatal brain, and they present a robust model to study brain disease in vitro.


Assuntos
Encéfalo/irrigação sanguínea , Células-Tronco Embrionárias Humanas/citologia , Organoides/irrigação sanguínea , Engenharia Tecidual/métodos , Animais , Barreira Hematoencefálica , Células Cultivadas , Humanos , Camundongos , Análise de Célula Única , Fatores de Transcrição/fisiologia
8.
Nat Commun ; 9(1): 5402, 2018 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-30573732

RESUMO

The fabrication of functional tissues is essential for clinical applications such as disease treatment and drug discovery. Recent studies have revealed that the mechanical environments of tissues, determined by geometric cell patterns, material composition, or mechanical properties, play critical roles in ensuring proper tissue function. Here, we propose an acoustophoretic technique using surface acoustic waves to fabricate therapeutic vascular tissue containing a three-dimensional collateral distribution of vessels. Co-aligned human umbilical vein endothelial cells and human adipose stem cells that are arranged in a biodegradable catechol-conjugated hyaluronic acid hydrogel exhibit enhanced cell-cell contacts, gene expression, and secretion of angiogenic and anti-inflammatory paracrine factors. The therapeutic effects of the fabricated vessel constructs are demonstrated in experiments using an ischemia mouse model by exhibiting the remarkable recovery of damaged tissue. Our study can be referenced to fabricate various types of artificial tissues that mimic the original functions as well as structures.


Assuntos
Isquemia/patologia , Engenharia Tecidual/métodos , Adipócitos/citologia , Animais , Vasos Sanguíneos , Técnicas de Cocultura , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Ácido Hialurônico , Hidrogel de Polietilenoglicol-Dimetacrilato , Camundongos , Camundongos Endogâmicos BALB C , Som , Células-Tronco/citologia , Engenharia Tecidual/instrumentação , Tecidos Suporte
9.
Commun Biol ; 1: 199, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30480100

RESUMO

Although tissue engineering using human-induced pluripotent stem cells is a promising approach for treatment of cardiovascular diseases, some limiting factors include the survival, electrical integration, maturity, scalability, and immune response of three-dimensional (3D) engineered tissues. Here we discuss these important roadblocks facing the tissue engineering field and suggest potential approaches to overcome these challenges.

10.
Korean Circ J ; 48(11): 974-988, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30334384

RESUMO

Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), which are collectively called pluripotent stem cells (PSCs), have emerged as a promising source for regenerative medicine. Particularly, human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have shown robust potential for regenerating injured heart. Over the past two decades, protocols to differentiate hPSCs into CMs at high efficiency have been developed, opening the door for clinical application. Studies further demonstrated therapeutic effects of hPSC-CMs in small and large animal models and the underlying mechanisms of cardiac repair. However, gaps remain in explanations of the therapeutic effects of engrafted hPSC-CMs. In addition, bioengineering technologies improved survival and therapeutic effects of hPSC-CMs in vivo. While most of the original concerns associated with the use of hPSCs have been addressed, several issues remain to be resolved such as immaturity of transplanted cells, lack of electrical integration leading to arrhythmogenic risk, and tumorigenicity. Cell therapy with hPSC-CMs has shown great potential for biological therapy of injured heart; however, more studies are needed to ensure the therapeutic effects, underlying mechanisms, and safety, before this technology can be applied clinically.

11.
Curr Cardiol Rep ; 20(6): 45, 2018 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-29730842

RESUMO

PURPOSE OF REVIEW: Human pluripotent stem cell-derived endothelial cells (hPSC-ECs) emerged as an important source of cells for cardiovascular regeneration. This review summarizes protocols for generating hPSC-ECs and provides an overview of the current state of the research in clinical application of hPSC-derived ECs. RECENT FINDINGS: Various systems were developed for differentiating hPSCs into the EC lineage. Stepwise two-dimensional systems are now well established, in which various growth factors, small molecules, and coating materials are used at specific developmental stages. Moreover, studies made significant advances in clinical applicability of hPSC-ECs by removing undefined components from the differentiation system, improving the differentiation efficiency, and proving their direct vascular incorporating effects, which contrast with adult stem cells and their therapeutic effects in vivo. Finally, by using biomaterial-mediated delivery, investigators improved the survival of hPSC-ECs to more than 10 months in ischemic tissues and described long-term behavior and safety of in vivo transplanted hPSC-ECs at the histological level. hPSC-derived ECs can be as a critical source of cells for treating advanced cardiovascular diseases. Over the past two decades, substantial improvement has been made in the differentiation systems and their clinical compatibility. In the near future, establishment of fully defined differentiation systems and proof of the advantages of biomaterial-mediated cell delivery, with some additional pre-clinical studies, will move this therapy into a vital option for treating those diseases that cannot be managed by currently available therapies.


Assuntos
Doenças Cardiovasculares/terapia , Diferenciação Celular , Células Progenitoras Endoteliais/citologia , Células Progenitoras Endoteliais/transplante , Células-Tronco Pluripotentes/citologia , Humanos , Modelos Biológicos , Regeneração , Medicina Regenerativa/métodos , Medicina Regenerativa/tendências
12.
Macromol Biosci ; 18(2)2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29285899

RESUMO

Stem cells are a promising cell source for regenerative medicine due to their differentiation and self-renewal capacities. In the field of regenerative medicine and tissue engineering, a variety of biomedical technologies have been tested to improve proangiogenic activities of stem cells. However, their therapeutic effect is found to be limited in the clinic because of cell loss, senescence, and insufficient therapeutic activities. To address this type of issue, advanced techniques for biomaterial synthesis and fabrication have been approached to mimic proangiogenic microenvironment and to direct proangiogenic activities. This review highlights the types of polymers and design strategies that have been studied to promote proangiogenic activities of stem cells. In particular, scaffolds, hydrogels, and surface topographies, as well as insight into their underlying mechanisms to improve proangiogenic activities are the focuses. The strategy to promote angiogenic activities of hMSCs by controlling substrate repellency is introduced, and the future direction is proposed.


Assuntos
Neovascularização Fisiológica , Polímeros/química , Células-Tronco/citologia , Técnicas de Cultura de Células
13.
Circulation ; 136(20): 1939-1954, 2017 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-28972000

RESUMO

BACKGROUND: Human pluripotent stem cell (hPSC)-derived endothelial cells (ECs) have limited clinical utility because of undefined components in the differentiation system and poor cell survival in vivo. Here, we aimed to develop a fully defined and clinically compatible system to differentiate hPSCs into ECs. Furthermore, we aimed to enhance cell survival, vessel formation, and therapeutic potential by encapsulating hPSC-ECs with a peptide amphiphile (PA) nanomatrix gel. METHODS: We induced differentiation of hPSCs into the mesodermal lineage by culturing on collagen-coated plates with a glycogen synthase kinase 3ß inhibitor. Next, vascular endothelial growth factor, endothelial growth factor, and basic fibroblast growth factor were added for endothelial lineage differentiation, followed by sorting for CDH5 (VE-cadherin). We constructed an extracellular matrix-mimicking PA nanomatrix gel (PA-RGDS) by incorporating the cell adhesive ligand Arg-Gly-Asp-Ser (RGDS) and a matrix metalloproteinase-2-degradable sequence. We then evaluated whether the encapsulation of hPSC-CDH5+ cells in PA-RGDS could enhance long-term cell survival and vascular regenerative effects in a hind-limb ischemia model with laser Doppler perfusion imaging, bioluminescence imaging, real-time reverse transcription-polymerase chain reaction, and histological analysis. RESULTS: The resultant hPSC-derived CDH5+ cells (hPSC-ECs) showed highly enriched and genuine EC characteristics and proangiogenic activities. When injected into ischemic hind limbs, hPSC-ECs showed better perfusion recovery and higher vessel-forming capacity compared with media-, PA-RGDS-, or human umbilical vein EC-injected groups. However, the group receiving the PA-RGDS-encapsulated hPSC-ECs showed better perfusion recovery, more robust and longer cell survival (> 10 months), and higher and prolonged angiogenic and vascular incorporation capabilities than the bare hPSC-EC-injected group. Surprisingly, the engrafted hPSC-ECs demonstrated previously unknown sustained and dynamic vessel-forming behavior: initial perivascular concentration, a guiding role for new vessel formation, and progressive incorporation into the vessels over 10 months. CONCLUSIONS: We generated highly enriched hPSC-ECs via a clinically compatible system. Furthermore, this study demonstrated that a biocompatible PA-RGDS nanomatrix gel substantially improved long-term survival of hPSC-ECs in an ischemic environment and improved neovascularization effects of hPSC-ECs via prolonged and unique angiogenic and vessel-forming properties. This PA-RGDS-mediated transplantation of hPSC-ECs can serve as a novel platform for cell-based therapy and investigation of long-term behavior of hPSC-ECs.


Assuntos
Células Endoteliais da Veia Umbilical Humana/transplante , Isquemia/terapia , Metaloproteinase 2 da Matriz/administração & dosagem , Nanoestruturas/administração & dosagem , Oligopeptídeos/administração & dosagem , Células-Tronco Pluripotentes/transplante , Animais , Diferenciação Celular/fisiologia , Terapia Baseada em Transplante de Células e Tecidos/métodos , Células Cultivadas , Células Endoteliais/fisiologia , Células Endoteliais/transplante , Membro Posterior/irrigação sanguínea , Células Endoteliais da Veia Umbilical Humana/fisiologia , Humanos , Isquemia/fisiopatologia , Masculino , Camundongos , Camundongos Nus , Células-Tronco Pluripotentes/fisiologia , Distribuição Aleatória , Resultado do Tratamento
14.
J Am Coll Cardiol ; 70(6): 766-775, 2017 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-28774384

RESUMO

Transplantations of various stem cells or their progeny have repeatedly improved cardiac performance in animal models of myocardial injury; however, the benefits observed in clinical trials have been generally less consistent. Some of the recognized challenges are poor engraftment of implanted cells and, in the case of human cardiomyocytes, functional immaturity and lack of electrical integration, leading to limited contribution to the heart's contractile activity and increased arrhythmogenic risks. Advances in tissue and genetic engineering techniques are expected to improve the survival and integration of transplanted cells, and to support structural, functional, and bioenergetic recovery of the recipient hearts. Specifically, application of a prefabricated cardiac tissue patch to prevent dilation and to improve pumping efficiency of the infarcted heart offers a promising strategy for making stem cell therapy a clinical reality.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos/métodos , Cardiopatias/terapia , Engenharia Tecidual/métodos , Humanos
15.
Theranostics ; 7(7): 2067-2077, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28638487

RESUMO

Cardiomyocytes (CMs) derived from human pluripotent stem cells (hPSCs) are considered a most promising option for cell-based cardiac repair. Hence, various protocols have been developed for differentiating hPSCs into CMs. Despite remarkable improvement in the generation of hPSC-CMs, without purification, these protocols can only generate mixed cell populations including undifferentiated hPSCs or non-CMs, which may elicit adverse outcomes. Therefore, one of the major challenges for clinical use of hPSC-CMs is the development of efficient isolation techniques that allow enrichment of hPSC-CMs. In this review, we will discuss diverse strategies that have been developed to enrich hPSC-CMs. We will describe major characteristics of individual hPSC-CM purification methods including their scientific principles, advantages, limitations, and needed improvements. Development of a comprehensive system which can enrich hPSC-CMs will be ultimately useful for cell therapy for diseased hearts, human cardiac disease modeling, cardiac toxicity screening, and cardiac tissue engineering.


Assuntos
Separação Celular/métodos , Miócitos Cardíacos/fisiologia , Células-Tronco Pluripotentes/fisiologia , Diferenciação Celular , Humanos
17.
Ann Vasc Surg ; 43: 288-295, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28479437

RESUMO

BACKGROUND: Postsurgical secondary lymphedema is usually a progressive and lifelong condition lacking any curative treatment. The aim of this study was to develop new, simple surgical mouse models of chronic lymphedema, better simulating chronic nature of human postsurgical lymphedema. METHODS: Two experimental mouse models of secondary lymphedema were created surgically without radiation by modifications of the previously described methods: the tail model and the hind limb model. Lymphedema formation was clinically assessed and quantitatively evaluated by measuring circumferences and limb volumes. Postmortem specimens were assessed histologically to examine the efficacy of the models. RESULTS: In the tail models, although a substantial frequency of tail necrosis (30.0%) was noted and the increase in circumference was maintained for only limited times postoperatively depending on the particular tail model, the overall success rate was 65.0%. In the mouse hind limb model, the overall success rate was 88.9%, and the increased circumference and limb volume were maintained over the entire study period of 8 weeks. The overall success rate of the mouse hind limb model was significantly higher than that of the mouse tail model(s). CONCLUSIONS: We have successfully established modified mouse tail and hind limb lymphedema models via only surgical techniques without radiation, which have characteristics of chronic secondary lymphedema. The mouse hind limb model has a higher success rate than the mouse tail model and has advantages of having the healthy contralateral hind limbs as an internal control.


Assuntos
Vasos Linfáticos/cirurgia , Linfedema/etiologia , Animais , Doença Crônica , Modelos Animais de Doenças , Feminino , Membro Posterior , Vasos Linfáticos/patologia , Linfedema/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Cauda , Fatores de Tempo
18.
Circ Res ; 120(5): 848-861, 2017 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-28003219

RESUMO

RATIONALE: Direct conversion or reprogramming of human postnatal cells into endothelial cells (ECs), bypassing stem or progenitor cell status, is crucial for regenerative medicine, cell therapy, and pathophysiological investigation but has remained largely unexplored. OBJECTIVE: We sought to directly reprogram human postnatal dermal fibroblasts to ECs with vasculogenic and endothelial transcription factors and determine their vascularizing and therapeutic potential. METHODS AND RESULTS: We utilized various combinations of 7 EC transcription factors to transduce human postnatal dermal fibroblasts and found that ER71/ETV2 (ETS variant 2) alone best induced endothelial features. KDR+ (kinase insert domain receptor) cells sorted at day 7 from ER71/ETV2-transduced human postnatal dermal fibroblasts showed less mature but enriched endothelial characteristics and thus were referred to as early reprogrammed ECs (rECs), and did not undergo maturation by further culture. After a period of several weeks' transgene-free culture followed by transient reinduction of ER71/ETV2, early rECs matured during 3 months of culture and showed reduced ETV2 expression, reaching a mature phenotype similar to postnatal human ECs. These were termed late rECs. While early rECs exhibited an immature phenotype, their implantation into ischemic hindlimbs induced enhanced recovery from ischemia. These 2 rECs showed clear capacity for contributing to new vessel formation through direct vascular incorporation in vivo. Paracrine or proangiogenic effects of implanted early rECs played a significant role in repairing hindlimb ischemia. CONCLUSIONS: This study for the first time demonstrates that ER71/ETV2 alone can directly reprogram human postnatal cells to functional, mature ECs after an intervening transgene-free period. These rECs could be valuable for cell therapy, personalized disease investigation, and exploration of the reprogramming process.


Assuntos
Técnicas de Reprogramação Celular/métodos , Células Endoteliais/fisiologia , Fibroblastos/fisiologia , Fatores de Transcrição/biossíntese , Animais , Diferenciação Celular/fisiologia , Células Cultivadas , Membro Posterior/irrigação sanguínea , Membro Posterior/fisiologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Isquemia/metabolismo , Masculino , Camundongos , Camundongos Nus , Neovascularização Fisiológica/fisiologia , Fatores de Transcrição/genética
19.
ACS Appl Mater Interfaces ; 8(8): 5178-87, 2016 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-26849167

RESUMO

Inflammatory responses play a critical role in tissue-implant interactions, often limiting current implant utility. This is particularly true for cardiovascular devices. Existing stent technology does little to avoid or mitigate inflammation or to influence the vasomotion of the artery after implantation. We have developed a novel endothelium-mimicking nanomatrix composed of peptide amphiphiles that enhances endothelialization while decreasing both smooth muscle cell proliferation and platelet adhesion. Here, we evaluated whether the nanomatrix could prevent inflammatory responses under static and physiological flow conditions. We found that the nanomatrix reduced monocyte adhesion to endothelial cells and expression of monocyte inflammatory genes (TNF-α, MCP-1, IL-1ß, and IL-6). Furthermore, the nitric-oxide releasing nanomatrix dramatically attenuated TNF-α-stimulated inflammatory responses as demonstrated by significantly reduced monocyte adhesion and inflammatory gene expression in both static and physiological flow conditions. These effects were abolished by addition of a nitric oxide scavenger. Finally, the nanomatrix stimulated vasodilation in intact rat mesenteric arterioles after constriction with phenylephrine, demonstrating the bioavailability and bioactivity of the nanomatrix, as well as exhibiting highly desired release kinetics. These results demonstrate the clinical potential of this nanomatrix by both preventing inflammatory responses and promoting vasodilation, critical improvements in stent and cardiovascular device technology.


Assuntos
Inflamação/prevenção & controle , Nanocompostos/uso terapêutico , Stents/efeitos adversos , Vasodilatação/efeitos dos fármacos , Animais , Artérias/efeitos dos fármacos , Artérias/patologia , Adesão Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Humanos , Inflamação/patologia , Monócitos/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Nanocompostos/química , Óxido Nítrico/metabolismo , Peptídeos/química , Adesividade Plaquetária/efeitos dos fármacos , Ratos
20.
Cell Transplant ; 25(2): 313-26, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-25975801

RESUMO

Recent evidence has suggested that diabetic neuropathy (DN) is pathophysiologically related to both impaired angiogenesis and a deficiency of neurotrophic factors in the nerves. It is widely known that vascular and neural growths are intimately associated. Mesenchymal stem cells (MSCs) promote angiogenesis in ischemic diseases and have neuroprotective effects, particularly on Schwann cells. Accordingly, we investigated whether DN could be improved by local transplantation of MSCs by augmenting angiogenesis and neural regeneration such as remyelination. In sciatic nerves of streptozotocin (STZ)-induced diabetic rats, motor and sensory nerve conduction velocities (NCVs) and capillary density were reduced, and axonal atrophy and demyelination were observed. After injection of bone marrow-derived MSCs (BM-MSCs) into hindlimb muscles, NCVs were restored to near-normal levels. Histological examination demonstrated that injected MSCs were preferentially and durably engrafted in the sciatic nerves, and a portion of the engrafted MSCs were distinctively localized close to vasa nervora of sciatic nerves. Furthermore, vasa nervora increased in density, and the ultrastructure of myelinated fibers in nerves was observed to be restored. Real-time RT-PCR experiments showed that gene expression of multiple factors involved in angiogenesis, neural function, and myelination were increased in the MSC-injected nerves. These findings suggest that MSC transplantation improved DN through direct peripheral nerve angiogenesis, neurotrophic effects, and restoration of myelination.


Assuntos
Medula Óssea/metabolismo , Diabetes Mellitus Experimental/patologia , Neuropatias Diabéticas/terapia , Células-Tronco Mesenquimais/citologia , Neovascularização Patológica/patologia , Animais , Células Cultivadas , Neuropatias Diabéticas/patologia , Masculino , Transplante de Células-Tronco Mesenquimais/métodos , Bainha de Mielina/metabolismo , Regeneração Nervosa/fisiologia , Ratos Wistar , Células de Schwann/metabolismo , Nervo Isquiático/patologia
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