ABSTRACT
In contrast to neonates and lower organisms, the adult mammalian heart lacks any capacity to regenerate following injury. The vast majority of our understanding of cardiac regeneration is based on research in young animals. Research in aged individuals is rare. This is unfortunate as aging induces many changes in the heart. The first part of this review covers the main technologies being pursued in the cardiac regeneration field and how they are impacted by the aging processes. The second part of the review covers the significant amount of aging-related research that could be used to aid cardiac regeneration. Finally, a perspective is provided to suggest how cardiac regenerative technologies can be improved by addressing aging-related effects.
ABSTRACT
The rapid and unprecedented climate changes driven by human-induced greenhouse gas emissions present a critical challenge for society today. However, the link between climate change and health remains inadequately explored in both literature and policy discussions. Thousands of individuals die each year in the United States due to climate-related factors, including extreme temperatures, severe weather, air pollution, and vector-borne diseases, and these health impacts disproportionately affect already vulnerable populations. Climate change is not just an environmental concern but also an imminent threat to individual and population health, as well as a major challenge to health equity. Moreover, the health sector significantly contributes to greenhouse gas emissions. Recognizing their roles as health care providers and contributors to the climate crisis, clinicians and health professionals have a moral obligation to emphasize the profound significance of climate impacts on human health and equity. This lecture provides an overview of efforts by the U.S. National Academy of Medicine and others to address the intersection of climate change and health, with an aim to raise awareness about the immediate threats to patient health and to build a proactive path forward for the health sector. The health sector must unite to collectively tackle these challenges, safeguard patient well-being, and promote the common good in the face of climate-induced health crises.
Subject(s)
Climate Change , Humans , Health Equity , United States , Delivery of Health CareABSTRACT
On June 24, 2022, the US Supreme Court's decision in Dobbs v Jackson Women's Health Organization marked the removal of the constitutional right to abortion in the USA, introducing a complex ethical and legal landscape for patients and providers. This shift has had immediate health and equity repercussions, but it is also crucial to examine the broader impacts on states, health-care systems, and society as a whole. Restrictions on abortion access extend beyond immediate reproductive care concerns, necessitating a comprehensive understanding of the ruling's consequences across micro and macro levels. To mitigate potential harm, it is imperative to establish a research agenda that informs policy making and ensures effective long-term monitoring and reporting, addressing both immediate and future impacts.
Subject(s)
Supreme Court Decisions , Women's Health , Female , Humans , Pregnancy , Abortion, Induced/legislation & jurisprudence , Abortion, Induced/ethics , Abortion, Legal/legislation & jurisprudence , Health Services Accessibility/legislation & jurisprudence , United States , Women's Health/legislation & jurisprudence , Women's Rights/legislation & jurisprudenceABSTRACT
The Dobbs v Jackson Women's Health Organization Supreme Court decision, which revoked the constitutional right to abortion in the USA, has impacted the national medical workforce. Impacts vary across states, but providers in states with restrictive abortion laws now must contend with evolving legal and ethical challenges that have the potential to affect workforce safety, mental health, education, and training opportunities, in addition to having serious impacts on patient health and far-reaching societal consequences. Moreover, Dobbs has consequences on almost every facet of the medical workforce, including on physicians, nurses, pharmacists, and others who work within the health-care system. Comprehensive research is urgently needed to understand the wide-ranging implications of Dobbs on the medical workforce, including legal, ethical, clinical, and psychological dimensions, to inform evidence-based policies and standards of care in abortion-restrictive settings. Lessons from the USA might also have global relevance for countries facing similar restrictions on reproductive care.
Subject(s)
Supreme Court Decisions , Female , Humans , Pregnancy , Abortion, Induced/legislation & jurisprudence , Abortion, Induced/ethics , Abortion, Legal/legislation & jurisprudence , Health Personnel , Health Workforce , United States , Women's HealthABSTRACT
In a previous report, we demonstrated that Cbx1, PurB and Sp3 inhibited cardiac muscle differentiation by increasing nucleosome density around cardiac muscle gene promoters. Since cardiac and skeletal muscle express many of the same proteins, we asked if Cbx1, PurB and Sp3 similarly regulated skeletal muscle differentiation. In a C2C12 model of skeletal muscle differentiation, Cbx1 and PurB knockdown increased myotube formation. In contrast, Sp3 knockdown inhibited myotube formation, suggesting that Sp3 played opposing roles in cardiac muscle and skeletal muscle differentiation. Consistent with this finding, Sp3 knockdown also inhibited various muscle-specific genes. The Cbx1, PurB and Sp3 proteins are believed to influence gene-expression in part by altering nucleosome position. Importantly, we developed a statistical approach to determine if changes in nucleosome positioning were significant and applied it to understanding the architecture of muscle-specific genes. Through this novel statistical approach, we found that during myogenic differentiation, skeletal muscle-specific genes undergo a set of unique nucleosome changes which differ significantly from those shown in commonly expressed muscle genes. While Sp3 binding was associated with nucleosome loss, there appeared no correlation with the aforementioned nucleosome changes. In summary, we have identified a novel role for Sp3 in skeletal muscle differentiation and through the application of quantifiable MNase-seq have discovered unique fingerprints of nucleosome changes for various classes of muscle genes during myogenic differentiation.
Subject(s)
Cell Differentiation , Muscle Development , Muscle, Skeletal , Nucleosomes , Promoter Regions, Genetic , Nucleosomes/metabolism , Nucleosomes/genetics , Animals , Cell Differentiation/genetics , Mice , Muscle, Skeletal/metabolism , Muscle Development/genetics , Cell Line , Sp3 Transcription Factor/metabolism , Sp3 Transcription Factor/genetics , Muscle Fibers, Skeletal/metabolismABSTRACT
We have demonstrated that directly reprogramming cardiac fibroblasts into new cardiomyocytes via miR combo improves cardiac function in the infarcted heart. However, major challenges exist with delivery and efficacy. During a screening based approach to improve delivery, we discovered that C166-derived EVs were effective delivery agents for miR combo both in vitro and in vivo. In the latter, EV mediated delivery of miR combo induced significant conversion of cardiac fibroblasts into cardiomyocytes (â¼20%), reduced fibrosis and improved cardiac function in a myocardial infarction injury model. When compared to lipid-based transfection, C166 EV mediated delivery of miR combo enhanced reprogramming efficacy. Improved reprogramming efficacy was found to result from a miRNA within the exosome: miR-148a-3p. The target of miR-148a-3p was identified as Mdfic. Over-expression and targeted knockdown studies demonstrated that Mdfic was a repressor of cardiomyocyte specific gene expression. In conclusion, we have demonstrated that C166-derived EVs are an effective method for delivering reprogramming factors to cardiac fibroblasts and we have identified a novel miRNA contained within C166-derived EVs which enhances reprogramming efficacy.
Subject(s)
Cellular Reprogramming , Fibroblasts , MicroRNAs , Myocytes, Cardiac , MicroRNAs/genetics , MicroRNAs/metabolism , Animals , Cellular Reprogramming/genetics , Myocytes, Cardiac/metabolism , Fibroblasts/metabolism , Mice , Myocardial Infarction/metabolism , Myocardial Infarction/genetics , Myocardial Infarction/pathology , Myocardial Infarction/therapy , Extracellular Vesicles/metabolism , Extracellular Vesicles/genetics , Exosomes/metabolism , Gene Expression Regulation , HumansABSTRACT
This Viewpoint discusses highlights from the National Academy of Medicine 2023 Annual Meeting Scientific Symposium that are representative of key gaps, trends, and opportunities in women's health.
Subject(s)
Women's Health , Humans , FemaleABSTRACT
Reprogramming scar fibroblasts into cardiomyocytes has been proposed to reverse the damage associated with myocardial infarction. However, the limited improvement in cardiac function calls for enhanced strategies. We reported enhanced efficacy of our miR reprogramming cocktail miR combo (miR-1, miR-133a, miR-208a, and miR-499) via RNA-sensing receptor stimulation. We hypothesized that we could combine RNA-sensing receptor activation with fibroblast reprogramming by chemically modifying miR combo. To test the hypothesis, miR combo was modified to enhance interaction with the RNA-sensing receptor Rig1 via the addition of a 5'-triphosphate (5'ppp) group. Importantly, when compared with unmodified miR combo, 5'ppp-modified miR combo markedly improved reprogramming efficacy in vitro. Enhanced reprogramming efficacy correlated with a type-I interferon immune response with strong and selective secretion of interferon ß (IFNß). Antibody blocking studies and media replacement experiments indicated that 5'ppp-miR combo utilized IFNß to enhance fibroblast reprogramming efficacy. In conclusion, miRs can acquire powerful additional roles through chemical modification that potentially increases their clinical applications.
ABSTRACT
RNA therapeutics hold significant promise in the treatment of cardiovascular diseases. RNAs are biologically diverse and functionally specific and can be used for gain- or loss-of-function purposes. The effectiveness of mRNA-based vaccines in the recent COVID-19 pandemic has undoubtedly proven the benefits of an RNA-based approach. RNA-based therapies are becoming more common as a treatment modality for cardiovascular disease. This is most evident in hypertension where several small interfering RNA-based drugs have proven to be effective in managing high blood pressure in several clinical trials. As befits a rapidly burgeoning field, there is significant interest in other classes of RNA. Revascularization of the infarcted heart through an mRNA drug is under clinical investigation. mRNA technology may provide the platform for the expression of paracrine factors for myocardial protection and regeneration. Emergent technologies on the basis of microRNAs and gene editing are tackling complex diseases in a novel fashion. RNA-based gene editing offers hope of permanent cures for monogenic cardiovascular diseases, and long-term control of complex diseases such as essential hypertension, as well. Likewise, microRNAs are proving effective in regenerating cardiac muscle. The aim of this review is to provide an overview of the current landscape of RNA-based therapies for the treatment of cardiovascular disease. The review describes the large number of RNA molecules that exist with a discussion of the clinical development of each RNA type. In addition, the review also presents a number of avenues for future development.
Subject(s)
Cardiovascular Diseases , Cardiovascular System , MicroRNAs , Humans , Cardiovascular Diseases/therapy , Cardiovascular Diseases/drug therapy , Pandemics , MicroRNAs/genetics , MicroRNAs/therapeutic use , RNA, Small Interfering/genetics , RNA, Messenger/genetics , RNA, Messenger/therapeutic useABSTRACT
Hypertension affects >1 billion people worldwide. Complications of hypertension include stroke, renal failure, cardiac hypertrophy, myocardial infarction, and cardiac failure. Despite the development of various antihypertensive drugs, the number of people with uncontrolled hypertension continues to rise. While the lack of compliance associated with frequent side effects to medication is a contributory issue, there has been a failure to consider the diverse nature of hypertensive populations. Instead, we propose that hypertension can only be truly managed by precision. A precision medicine approach would consider each patient's unique factors. In this review, we discuss the progress toward precision medicine for hypertension with more predictiveness and individualization of treatment. We will highlight the advances in data science, omics (genomics, metabolomics, proteomics, etc), artificial intelligence, gene therapy, and gene editing and their application to precision hypertension.
Subject(s)
Artificial Intelligence , Hypertension , Humans , Hypertension/genetics , Hypertension/therapy , Hypertension/complications , Antihypertensive Agents , Genomics , ProteomicsABSTRACT
The social benefit of technologies is frequently unevenly realized across the United States. Rural communities, individuals with disabilities, and historically marginalized groups face out-of-reach costs or lack access to products that meet their needs. Blame is typically placed on complicated regulatory processes or complex delivery systems, but this response neglects the problem that equity is not baked into the nation's innovation process at any stage. The United States needs to rethink its entire innovation ecosystem to incorporate equity as a foundational guiding principle-from research design and funding requirements to policies and regulations that govern the delivery and oversight of new products to the public.
ABSTRACT
Directly reprogramming fibroblasts into cardiomyocytes improves cardiac function in the infarcted heart. However, the low efficacy of this approach hinders clinical applications. Unlike the adult mammalian heart, the neonatal heart has an intrinsic regenerative capacity. Consequently, we hypothesized that birth imposes fundamental changes in cardiac fibroblasts which limit their regenerative capabilities. In support, we found that reprogramming efficacy in vitro was markedly lower with fibroblasts derived from adult mice versus those derived from neonatal mice. Notably, fibroblasts derived from adult mice expressed significantly higher levels of pro-angiogenic genes. Moreover, under conditions that promote angiogenesis, only fibroblasts derived from adult mice differentiated into tube-like structures. Targeted knockdown screening studies suggested a possible role for the transcription factor Epas1. Epas1 expression was higher in fibroblasts derived from adult mice, and Epas1 knockdown improved reprogramming efficacy in cultured adult cardiac fibroblasts. Promoter activity assays indicated that Epas1 functions as both a transcription repressor and an activator, inhibiting cardiomyocyte genes while activating angiogenic genes. Finally, the addition of an Epas1 targeting siRNA to the reprogramming cocktail markedly improved reprogramming efficacy in vivo with both the number of reprogramming events and cardiac function being markedly improved. Collectively, our results highlight differences between neonatal and adult cardiac fibroblasts and the dual transcriptional activities of Epas1 related to reprogramming efficacy.
Subject(s)
Cellular Reprogramming , Myocytes, Cardiac , Transcription Factors , Animals , Mice , Fibroblasts/cytology , Gene Expression Regulation , Myocytes, Cardiac/cytology , Transcription Factors/metabolism , Animals, NewbornABSTRACT
This Viewpoint from the president of the National Academy of Medicine looks back at the academy's accomplishments and looks forward to the possibilities it hopes to achieve to better medicine and society.
Subject(s)
Medicine , National Academies of Science, Engineering, and Medicine, U.S., Health and Medicine Division , Academies and Institutes , United States , Health/trends , ForecastingABSTRACT
Current methods to generate cardiomyocytes from induced pluripotent stem cells (iPSc) utilize broad-spectrum pharmacological inhibitors. These methods give rise to cardiomyocytes which are typically immature. Since we have recently demonstrated that cardiomyogenesis in vitro and in vivo requires Sfrp2, we asked if Sfrp2 would drive differentiation of human iPSc into cardiomyocytes. Indeed, we found that Sfrp2 induced robust cardiac differentiation. Importantly, replacement of broad spectrum pharmacological inhibitors with Sfrp2 gave rise to mature cardiomyocytes as evidenced by their sarcomere structure, electrophysiological profiles, and ability to form gap junctions.
Subject(s)
Induced Pluripotent Stem Cells , Myocytes, Cardiac , Humans , Cell Differentiation , Electrophysiological Phenomena , Membrane ProteinsABSTRACT
We discovered that innate immunity plays an important role in the reprogramming of fibroblasts into cardiomyocytes. In this report, we define the role of a novel retinoic acid-inducible gene 1 Yin Yang 1 (Rig1:YY1) pathway. We found that fibroblast to cardiomyocyte reprogramming efficacy was enhanced by specific Rig1 activators. To understand the mechanism of action, we performed various transcriptomic, nucleosome occupancy, and epigenomic approaches. Analysis of the datasets indicated that Rig1 agonists had no effect on reprogramming-induced changes in nucleosome occupancy or loss of inhibitory epigenetic motifs. Instead, Rig1 agonists were found to modulate cardiac reprogramming by promoting the binding of YY1 specifically to cardiac genes. To conclude, these results show that the Rig1:YY1 pathway plays a critical role in fibroblast to cardiomyocyte reprogramming.