Bearing My Heart: The Role of Extracellular Matrix on Cardiac Development, Homeostasis, and Injury Response

The extracellular matrix (ECM) is an essential component of the heart that imparts fundamental cellular processes during organ development and homeostasis. Most cardiovascular diseases involve severe remodeling of the ECM, culminating in the formation of fibrotic tissue that is deleterious to organ function. Treatment schemes effective at managing fibrosis and promoting physiological ECM repair are not yet in reach. Of note, the composition of the cardiac ECM changes significantly in a short period after birth, concurrent with the loss of the regenerative capacity of the heart. This highlights the importance of understanding ECM composition and function headed for the development of more efficient therapies. In this review, we explore the impact of ECM alterations, throughout heart ontogeny and disease, on cardiac cells and debate available approaches to deeper insights on cell–ECM interactions, toward the design of new regenerative therapies.This work was funded by the European Regional Development Fund (ERDF) through COMPETE 2020, Portugal 2020, and by the FCT (Fundação para a Ciência e Tecnologia) (POCI-01-0145-FEDER-030985) and by the FCT/Ministério da Ciência, Tecnologia e Inovação in the framework of individual funding (CEECINST/00091/2018) to DN

Establishing a link between endothelial cell metabolism and vascular behaviour in a type 1 diabetes mouse model

Background/Aims: Vascular complications contribute significantly to the extensive morbidity and mortality rates observed in people with diabetes. Despite well known that the diabetic kidney and heart exhibit imbalanced angiogenesis, the mechanisms implicated in this angiogenic paradox remain unknown. In this study, we examined the angiogenic and metabolic gene expression profile (GEP) of endothelial cells (ECs) isolated from a mouse model with type1 diabetes mellitus (T1DM). Methods: ECs were isolated from kidneys and hearts of healthy and streptozocin (STZ)-treated mice. RNA was then extracted for molecular studies. GEP of 84 angiogenic and 84 AMP-activated Protein Kinase (AMPK)-dependent genes were examined by microarrays. Real time PCR confirmed the changes observed in significantly altered genes. Microvessel density (MVD) was analysed by immunohistochemistry, fibrosis was assessed by the Sirius red histological staining and connective tissue growth factor (CTGF) was quantified by ELISA. Results: The relative percentage of ECs and MVD were increased in the kidneys of T1DM animals whereas the opposite trend was observed in the hearts of diabetic mice. Accordingly, the majority of AMPK-associated genes were upregulated in kidneys and downregulated in hearts of these animals. Angiogenic GEP revealed significant differences in Tgfß, Notch signaling and Timp2 in both diabetic organs. These findings were in agreement with the angiogenesis histological assays. Fibrosis was augmented in both organs in diabetic as compared to healthy animals. Conclusion: Altogether, our findings indicate, for the first time, that T1DM heart and kidney ECs present opposite metabolic cues, which are accompanied by distinct angiogenic patterns. These findings enable the development of innovative organ-specific therapeutic strategies targeting diabetic-associated vascular disorders.This work was supported by CAPES (Sciences without Borders - Full Doctorate Fellowship – Process 10010-13-0); FEDER funds by COMPETE: [POCI-01-0145-FEDER-007440, POCI-01-0145-FEDER-016385]; NORTE2020 [NORTE-01-0145FEDER-000012]; HealthyAging2020 [CENTRO-01-0145-FEDER-000012-N2323]; FCT - Fundação para a Ciência e a Tecnologia [UID/BIM/04293/2013, EXPL/BIM-MED/0492/2012, SFRH/BPD/88745/2012, SFRH/BD/111799/2015]; Claude Pepper Older Americans Independence Center; grant: P30 AG028718, NIGMS Award P20GM109096; European Structural and Investment Funds (ESIF). AUTHOR CONTRIBUTION: CS and RS participated in the design and conception of the study; CS performed the whole laboratory and statistical analyses and drafted the manuscript; VSP, PPO, DSN carried out the FACS assay design and data acquisition, as well as the interpretation of FACS data; SA advised and performed microarray and RT-PCR assays; IR headed the parafin embedded tissue and histologial staining; SG, EC were responsible for the animal studies and immunohistochemistry analyses; RC advised the methodological laboratorial analysis and animal studies; RS and EC critically revised the manuscript for important intellectual content. All authors were involved in drafting and revising the article. All authors read and approved the final version of the manuscript

Consistent Long-Term Therapeutic Efficacy of Human Umbilical Cord Matrix-Derived Mesenchymal Stromal Cells After Myocardial Infarction Despite Individual Differences and Transient Engraftment

Human mesenchymal stem cells gather special interest as a universal and feasible add-on therapy for myocardial infarction (MI). In particular, human umbilical cord matrix-derived mesenchymal stromal cells (UCM-MSC) are advantageous since can be easily obtained and display high expansion potential. Using isolation protocols compliant with cell therapy, we previously showed UCM-MSC preserved cardiac function and attenuated remodeling 2 weeks after MI. In this study, UCM-MSC from two umbilical cords, UC-A and UC-B, were transplanted in a murine MI model to investigate consistency and durability of the therapeutic benefits. Both cellular products improved cardiac function and limited adverse cardiac remodeling 12 weeks post-ischemic injury, supporting sustained and long-term beneficial therapeutic effect. Donor associated variability was found in the modulation of cardiac remodeling and activation of the Akt-mTOR-GSK3ß survival pathway. In vitro, the two cell products displayed similar ability to induce the formation of vessel-like structures and comparable transcriptome in normoxia and hypoxia, apart from UCM-MSCs proliferation and expression differences in a small subset of genes associated with MHC Class I. These findings support that UCM-MSC are strong candidates to assist the treatment of MI whilst calling for the discussion on methodologies to characterize and select best performing UCM-MSC before clinical application.This work was funded by European Structural and Investment Funds (ESIF), under Lisbon Portugal Regional Operational Programme and National Funds through Fundação para a Ciência e Tecnologia (FCT) ([POCI-01-0145-FEDER-030985], [POCI-01-0145-FEDER-016385]); by FCT/Ministério da Ciência, Tecnologia e Inovação in the framework of individual funding [CEECINST/00091/2018] to DN and by QREN funds through the project ClinUCX (QREN 30196) and individual fellowships: [PD/BD/127997/2016] to TL, [SFRH/BD/144490/2019] to RG and [SFRH/BD/111799/2015] to VS-P. The funding bodies other than ECBio had no role in design, in the collection, analysis, and interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication

Host Plant Record for the Fruit Flies, Anastrepha fumipennis and A. nascimentoi (Diptera, Tephritidae)

The first host plant record for Anastrepha fumipennis Lima (Diptera: Tephritidae) in Geissospermum laeve (Vell.) Baill (Apocynaceae) and for A. nascimentoi Zucchi found in Cathedra bahiensis Sleumer (Olacaceae) was determined in a host plant survey of fruit flies undertaken at the “Reserva Natural da Companhia Vale do Rio Doce”. This reserve is located in an Atlantic Rain Forest remnant area, in Linhares county, state of Espírito Santo, Brazil. The phylogenetic relationships of Anastrepha species and their hosts are discussed. The occurrence of these fruit fly species in relation to the distribution range of their host plants is also discussed

Evaluation of prenatal care in unit with family health strategy

We analyzed prenatal care (PN) provided at a unit of the Family Health Strategy Service in São Paulo, according to the indicators of the Program for the Humanization of Prenatal and Birth (PHPB). We compared adequacy of PN in terms of sociodemographic variables, procedures, examinations and maternal and perinatal outcomes. Cross-sectional study with data from records of 308 pregnant women enrolled in 2011. We observed early initiation of PN (82.1%), conducting of a minimum of six consultations (84.1%), puerperal consultation (89.0%); to the extent that there is a sum of the actions, there is a significant drop in the proportion of adequacy. Prenatal care was adequate for 67.9%, with a significant difference between adequacy groups in relation to gestational age and birth weight. Prenatal care deficiencies exist, especially in regards to registration of procedures, exams and immunization. The difference between adequacy groups with respect to perinatal outcomes reinforces the importance of prenatal care that adheres to the parameters of the PHPB

Avaliação das estratégias de acolhimento na Unidade de Terapia Intensiva

Trata-se de uma pesquisa qualitativa, realizada na Unidade de Terapia Intensiva (UTI) adulto de um hospital público no Sul do Brasil, que teve como objetivo avaliar as estratégias de acolhimento implementadas. Participaram 13 pacientes e 23 familiares. A coleta foi realizada de julho a outubro de 2008, com entrevistas semiestruturadas e gravadas. Para análise dos dados, utilizou-se o Discurso do Sujeito Coletivo. As informações deram origem a dois discursos: a família percebe o acolhimento e o paciente considera a equipe da UTI atenciosa. Ao incluir a família no cuidado como cliente da enfermagem, os familiares sentiram-se seguros e confiantes. Ao avaliar os resultados alcançados, destaca-se que, ao assumirem o compromisso e a responsabilidade de transformações da prática assistencial, os enfermeiros experienciaram um novo olhar para o cuidado em UTI, com enfoque no ser humano, aliando o acolhimento ao modelo assistencial que privilegia a objetividade do cuidado.Investigación cualitativa realizada en Unidad de Terapia Intensiva (UTI) de adultos de hospital público del Sur de Brasil, que objetivó evaluar las estrategias de recepción implementadas. Participaron 13 pacientes y 23 familiares. La recolección de datos se realizó entre julio y octubre de 2008, con entrevistas semiestructuradas y grabadas. Para análisis de datos, se usó Discurso del Sujeto Colectivo. Las informaciones originaron dos discursos: la familia percibe la recepción y el paciente considera al equipo de UTI atento. Al incluir a la familia en el cuidado como pacientes de enfermería, los familiares se sintieron seguros y confiados. Al evaluar los resultados alcanzados, se destaca que al asumir el compromiso y responsabilidad de transformaciones de la práctica de atención, los enfermeros experimentaron nueva visión para el cuidado en UTI, con enfoque en el ser humano, aliando la recepción al modelo de atención que privilegia la objetividad del cuidado.This qualitative study was performed at the adult Intensive Care Unit (ICU) of a public hospital in Southern Brazil with the objective to evaluate the implemented welcoming strategies. Participants included 13 patients and 23 relatives. Data collection was performed from July to October 2008, utilizing semi-structured interviews. All interviews were recorded. Data analysis was performed using the Collective Subject Discourse. The collected information yielded two discourses: the family recognized the welcoming strategies and the patients found the ICU team to be considerate. By including the family as a client of nursing care, relatives felt safe and confident. Results show that by committing to the responsibility of making changes in heath care practices, nurses experience a novel outlook towards ICU care, focused on human beings and associating the welcoming to the health care model that promotes the objectivity of care

A microRNA program regulates the balance between cardiomyocyte hyperplasia and hypertrophy and stimulates cardiac regeneration

Myocardial regeneration is restricted to early postnatal life, when mammalian cardiomyocytes still retain the ability to proliferate. The molecular cues that induce cell cycle arrest of neonatal cardiomyocytes towards terminally differentiated adult heart muscle cells remain obscure. Here we report that the miR-106b~25 cluster is higher expressed in the early postnatal myocardium and decreases in expression towards adulthood, especially under conditions of overload, and orchestrates the transition of cardiomyocyte hyperplasia towards cell cycle arrest and hypertrophy by virtue of its targetome. In line, gene delivery of miR-106b~25 to the mouse heart provokes cardiomyocyte proliferation by targeting a network of negative cell cycle regulators including E2f5, Cdkn1c, Ccne1 and Wee1. Conversely, gene-targeted miR-106b~25 null mice display spontaneous hypertrophic remodeling and exaggerated remodeling to overload by derepression of the prohypertrophic transcription factors Hand2 and Mef2d. Taking advantage of the regulatory function of miR-106b~25 on cardiomyocyte hyperplasia and hypertrophy, viral gene delivery of miR-106b~25 provokes nearly complete regeneration of the adult myocardium after ischemic injury. Our data demonstrate that exploitation of conserved molecular programs can enhance the regenerative capacity of the injured heart.E.D. is supported by a VENI award 916-150-16 from the Netherlands Organization for Health Research and Development (ZonMW), an EMBO Long-term Fellowship (EMBO ALTF 848-2013) and a FP7 Marie Curie Intra-European Fellowship (Project number 627539). V.S.P. was funded by a fellowship from the FCT/ Ministério da Ciência, Tec-nologia e Inovação SFRH/BD/111799/2015. P.D.C.M. is an Established Investigator of the Dutch Heart Foundation. L.D.W. acknowledges support from the Dutch CardioVascular Alliance (ARENA-PRIME). L.D.W. was further supported by grant 311549 from the European Research Council (ERC), a VICI award 918-156-47 from the Dutch Research Council and Marie Sklodowska-Curie grant agreement no. 813716 (TRAIN-HEART)