Richard T Lee's research while affiliated with Harvard University and other places
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Publications (414)
Patients with mitochondrial disorders present with clinically diverse symptoms, largely driven by
heterogeneous mutations in mitochondrial-encoded and nuclear-encoded mitochondrial genes.
These mutations ultimately lead to complex biochemical disorders with a myriad of clinical
manifestations, often accumulating during childhood on into adulthood,...
Since the exogenous administration of GDF11, a TGF-ß superfamily member, was reported to have beneficial effects in some models of human disease, there have been many research studies in GDF11 biology. However, many studies have now confirmed that exogenous administration of GDF11 can improve physiology in disease models, including cardiac fibrosis...
Background: The spatial organization of the diverse cells in the heart shapes biological function. For instance, during the inflammatory and fibrotic processes that are central to heart disease, many cells act mainly within their local microenvironment. Recent studies using single-cell RNA sequencing (scRNA-seq) have provided a detailed list of the...
Introduction: Regenerated cardiomyocytes (CMs) derived from human-induced pluripotent stem cells (hiPS-CMs) have potential for improving deficits in cardiac function due to loss of cardiomyocytes. However, hiPS-CMs are immature relative to adult cardiomyocytes. Here, we demonstrate that injecting CMs with self-assembling peptide (SAP) nanofibers ca...
Glucagon signaling is essential for maintaining normoglycemia in mammals. The arrestin fold superfamily of proteins controls the trafficking, turnover, and signaling of transmembrane receptors, as well as other intracellular signaling functions. Further investigation is needed to understand the in vivo functions of the Arrestin Domain Containing 4...
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A potential mediatory role for systemic inflammation in the association between subclinical atherosclerosis and Grim epigenetic age acceleration, identified by multi-omics analyses utilizing participants in the Progression of Early Subclinical Atherosclerosis (PESA) study.
Corresponding Author
Parkinson’s disease (PD) is a complex neurodegenerative disease with etiology rooted in genetic vulnerability and environmental factors. Here we combine quantitative epidemiologic study of pesticide exposures and PD with toxicity screening in dopaminergic neurons derived from PD patient induced pluripotent stem cells (iPSCs) to identify Parkinson’s...
Clinical translation of stem cell therapies for heart disease requires electrical integration of transplanted cardiomyocytes. Generation of electrically matured human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) is critical for electrical integration. Here, we found that hiPSC-derived endothelial cells (hiPSC-ECs) promoted the e...
Growth differentiation factor 11 (GDF11) and GDF8 (MSTN) are closely related TGF-β family proteins that interact with nearly identical signaling receptors and antagonists. However, GDF11 appears to activate SMAD2/3 more potently than GDF8 in vitro and in vivo. The ligands possess divergent structural properties, whereby substituting unique GDF11 am...
DNA damage causes genomic instability underlying many human diseases. Traditional approaches to DNA damage analysis provide minimal insights into the spectrum of disease-driving DNA lesions and the mechanisms causing imbalances in damage formation and repair. Here we used untargeted mass spectrometry-based adductomics to discover 114 putative DNA l...
Background:
The human heart has limited capacity to generate new cardiomyocytes and this capacity declines with age. Because loss of cardiomyocytes may contribute to heart failure, it is crucial to explore stimuli of endogenous cardiac regeneration to favorably shift the balance between loss of cardiomyocytes and the birth of new cardiomyocytes in...
Significance:
Thioredoxin interacting protein (TXNIP) is a member of the arrestin foldsuperfamily with important cellular functions, including cellular transport, mitochondrial energy generation and protein cycling. It is the only arrestin-domain protein known to covalently bind to thioredoxin and plays roles in glucose metabolism, inflammation, a...
Growth differentiation factor 11 (GDF11) and GDF8 (MSTN) are closely related TGFβ family proteins that interact with nearly identical signaling receptors and antagonist proteins. However, GDF11 appears to activate SMAD2/3 in vitro and in vivo more potently than GDF8. The ligands possess divergent structural properties, whereby substituting unique G...
There is considerable variability in the susceptibility and progression for COVID-19 and it appears to be strongly correlated with age, gender, ethnicity and pre-existing health conditions. However, to our knowledge, cohort studies of COVID-19 in clinically vulnerable groups are lacking. Host genetics has also emerged as a major risk factor for COV...
Fibrosis is a pathological hallmark of systemic sclerosis (SSc), a deadly autoimmune disease affecting the connective tissues of multiple organs. However, the immune mechanisms underlying fibrosis and SSc remain unclear. To determine the initiating immune pathway in fibrosis, we investigated the role of type 2 alarmin cytokines in the mouse model o...
Cardiovascular disease is a leading cause of death worldwide, and thus there remains great interest in regenerative approaches to treat heart failure. In the past 20 years, the field of heart regeneration has entered a renaissance period with remarkable progress in the understanding of endogenous heart regeneration, stem cell differentiation for ex...
Clinical translation of stem cell therapies for heart disease is limited by a risk of potentially life-threatening ventricular arrhythmias seen following cardiomyocyte delivery in large animal models. Enhancing cardiomyocyte maturation may reduce this arrhythmogenic risk by reducing automaticity of delivered cardiomyocytes. We tested whether human...
The adult human heart is unable to regenerate after a major injury, while some vertebrates including neonatal mice heart possess substantial heart regeneration. In a previous multi-species transcriptome study, we identified Complement receptors C5aR1 and C3aR1 as evolutionarily conserved upregulated genes during the early phase of heart regeneratio...
Directed differentiation of human pluripotent stem cells (PSC) into cardiomyocytes via manipulation of Wnt signaling leads to generation of immature cardiomyocytes, more closely resembling a fetal state. It has become increasingly apparent that metabolic parameters regulate of cardiomyocyte maturation. The forkhead box (FOX) family of transcription...
Adult stem cells maintain regenerative tissue structure and function by producing tissue-specific progeny, but the factors that preserve their tissue identities are not well understood. The small and large intestines differ markedly in cell composition and function, reflecting their distinct stem cell populations. Here we show that SATB2, a colon-r...
Background
Host genetics play a major role in COVID-19 susceptibility and severity. Here, we analyse an ethnically diverse cohort of National Health Service (NHS) patients in the United Kingdom (UK) to assess the association between variants in the ACE2 locus and COVID-19 risk.
Methods
We analysed whole-genome sequencing (WGS) data of 6,274 partici...
Glucose is arguably the most important molecule in metabolism, and its dysregulation underlies diabetes. We describe a family of single-wavelength genetically encoded glucose sensors with a high signal-to-noise ratio, fast kinetics, and affinities varying over four orders of magnitude (1 μM to 10 mM). The sensors allow mechanistic characterization...
Cellular senescence is a state of irreversible cell cycle arrest associated with ageing. Senescence of different cardiac cell types can direct the pathophysiology of cardiovascular diseases such as atherosclerosis, myocardial infarction, and cardiac fibrosis. While age-related telomere shortening represents a major cause of replicative senescence,...
Current methods to differentiate cardiomyocytes from human pluripotent stem cells (PSCs) inadequately recapitulate complete development and result in PSC-derived cardiomyocytes (PSC-CMs) with an immature or fetal-like phenotype. Embryonic and fetal development are highly dynamic periods during which the developing embryo or fetus is exposed to chan...
Increased consumption of fats and added sugars has been associated with an increase in metabolic syndromes. Here we show that mice chronically fed an energy rich diet (ERD) with high fat and moderate sucrose (HFD) have enhanced absorption of a gastrointestinal fructose load, and this required expression of the arrestin-domain protein Txnip in intes...
Heart failure with preserved ejection fraction (HFpEF) is the most common type of HF in older adults. Although no pharmacological therapy has yet improved survival in HFpEF, exercise training (ExT) has emerged as the most effective intervention to improving functional outcomes in this age‐related disease. The molecular mechanisms by which ExT induc...
The molecular mechanisms that control glucose uptake into the cells are not yet completely defined. The Arrestin superfamily of proteins controls the inactivation, degradation and signaling of trans‐membrane receptors. Several members of the family, including Arrestin domain containing 3 and TXNIP, are now known to have important roles in metabolis...
Insulin resistance is associated with aging in mice and humans. We have previously shown that administration of recombinant GDF11 (rGDF11) to aged mice alters aging phenotypes in the brain, skeletal muscle, and heart. While the closely related protein GDF8 has a role in metabolism, limited data are available on the potential metabolic effects of GD...
Significance
Insulin resistance in liver is a key component in the pathogenesis of type 2 diabetes, obesity-associated nonalcoholic fatty liver disease, and metabolic syndrome. Here we demonstrate that hepatic expression of Arrdc3 , a molecular adaptor previously linked to human obesity, is potently induced by physiological insulin and obesity-rela...
Today, cell replacement therapy using pluripotent stem cell-derived cardiomyocytes (PSC-CMs) remains a research endeavor, with several hurdles that must be overcome before delivery of PSC-CMs can become a therapeutic reality. In this review, we highlight major findings to date from pre-clinical studies involving delivery of PSC-CMs and consider rem...
Recent advances in CRISPR/Cas gene editing technology have significantly expanded the possibilities and accelerated the pace of creating genetically engineered animal models. However, CRISPR/Cas-based strategies designed to precisely edit the genome can often yield unintended outcomes. Here, we report the use of zygotic CRISPR/Cas9 injections to ge...
Background:
Current differentiation protocols to produce cardiomyocytes from human induced pluripotent stem cells (iPSCs) are capable of generating highly pure cardiomyocyte populations as determined by expression of cardiac troponin T. However, these cardiomyocytes remain immature, more closely resembling the fetal state, with a lower maximum con...
The adult mammalian heart is incapable of clinically relevant regeneration. The regenerative deficit in adult mammalian heart contrasts with the fetal and neonatal heart, which demonstrate substantial regenerative capacity after injury. This deficiency in adult mammals is attributable to the lack of resident stem cells after birth, combined with an...
Key Points
Genetic deletion of Gdf11 does not affect red blood cell formation during homeostasis or after transplant. Hematopoietic stem cell function is preserved in mice lacking Gdf11 expression within the blood lineage.
The adult myocardium has a limited regenerative capacity following heart injury, and the lost cells are primarily replaced by fibrotic scar tissue. Suboptimal efficiency of current clinical therapies to resurrect the infarcted heart results in injured heart enlargement and remodeling to maintain its physiological functions. These remodeling process...
Objectives:
Growth differentiation factor (GDF) 11 has been shown to reduce cardiac hypertrophy in mice. Low levels of GDF-11 are associated with cardiac hypertrophy in humans. The authors hypothesized that plasma GDF-11 level is decreased in cats with hypertrophic cardiomyopathy (HCM). Given the close homology between GDF-11 and myostatin/GDF-8,...
Calorie restriction (CR) improved healthspan in two longitudinal studies in nonhuman primates (NHPs), yet only the University of Wisconsin (UW) study demonstrated an increase in survival in CR monkeys relative to controls; the National Institute on Aging (NIA) study did not. Here, analysis of left ventricle samples showed that CR did not reduce car...
Administration of active growth differentiation factor 11 (GDF11) to aged mice can reduce cardiac hypertrophy, and low serum levels of GDF11 measured together with the related protein, myostatin (also known as GDF8), predict future morbidity and mortality in coronary heart patients. Using mice with a loxP-flanked ("floxed") allele of Gdf11 and Myh6...
Randomized clinical trials initially used heart failure (HF) patients with low left ventricular ejection fraction (LVEF) to select study populations with high risk to enhance statistical power. However, this use of LVEF in clinical trials has led to oversimplification of the scientific view of a complex syndrome. Descriptive terms such as 'HFrEF' (...
Calorie restriction (CR) improved healthspan in two longitudinal studies in nonhuman primates (NHPs) aimed at investigating the effect of this nutritional intervention on markers of health and survival. However, only the University of Wisconsin (UW) study demonstrated an increase in survival in CR monkeys relative to controls; the National Institut...
Mast cell (MC)mediator release after crosslinking of surface-bound IgE antibody by ingested antigen underlies food allergy. However, IgE antibodies are not uniformly associated with food allergy, and intestinal MC load is an important determinant. Atopic dermatitis (AD), characterized by pruritis and cutaneous sensitization to allergens, including...
Glucose is arguably the most important molecule in metabolism, and its mismanagement underlies diseases of vast societal import, most notably diabetes. Although glucose-related metabolism has been the subject of intense study for over a century, tools to track glucose in living organisms with high spatio-temporal resolution are lacking. We describe...
Microvascular dysfunction in the heart and its association with periarteriolar fibrosis may contribute to the diastolic dysfunction seen in heart failure with preserved ejection fraction. Interleukin-33 (IL-33) prevents global myocardial fibrosis in a pressure overloaded left ventricle by acting via its receptor, ST2 (encoded by the gene, Il1rl1);...
Significance
Chronic inflammatory diseases are well-recognized causes of cancer and account for up to 20% of all cancer deaths worldwide. However, the mechanism that initiates the development of a tumor-promoting immune environment in chronic inflammation is not known. Using mouse models of chronic skin and colon inflammation and human samples, we...
Supporting information data.
This file contains the list of primers used in this study and supplementary materials and methods.
(PDF)
JAK/STAT inhibition does not affect islet viability.
Whole pancreatic rat islets were cultured for a period of 14 days with or without ApoE together with JAK/STAT inhibitors. Comparable levels of viable and dead cells were detected between the two groups. Scale bar, 50 uM. Data presented as mean ± SEM, where n.s. means not significant (n = 10).
(EP...
The in vivo microenvironment of tissues provides myriad unique signals to cells. Thus, following isolation, many cell types change in culture, often preserving some but not all of their in vivo characteristics in culture. At least some of the in vivo microenvironment may be mimicked by providing specific cues to cultured cells. Here, we show that a...
Effect of ApoE on islets cultured in suspension and on human islets.
A) Whole human pancreatic islets were cultured for a period of 7 days under physiological glucose (11 mM) conditions with or without ApoE. Comparable levels of key β-cell markers was observed.
B) Human islets were cultured for 7 days in 804G coated plates with and without ApoE. Ea...
Whole islet gene expression profile is lost in adherent cultures in vitro.
Gene expression analysis of β-cell transcription factors from rat pancreatic whole islets cultured under low glucose (5 mM) conditions for 2 weeks shows reduced gene expression over time (n = 4).
(EPS)
ApoE Treatment does not stimulate islet cell proliferation.
Whole rat pancreatic islets were cultured for a period of 14 days with or without ApoE together with BrdU. Very low levels of BrdU positive cells were detected in both groups. Scale bar, 50 uM. Data presented as mean ± SEM, where n.s. means not significant (n = 10).
(EPS)
ApoE enhances islet gene expression profile in vitro.
A) Whole rat pancreatic islets were cultured for a period of 14 days with or without ApoE under low glucose (5 mM) conditions. ApoE significantly increased the expression of key β-cell markers including Ins2, Ucn3, Glut2, Nkx2.2, Nkx6.1, Pcsk1, Sur1 and Pc. B) Whole rat pancreatic Islets were cu...
Caloric restriction (CR) has been shown to decrease aging and increase the lifespan of several model organisms. However, in two on-going independent, long-term CR studies in non-human primates (NHP) at the National Institute of Aging (NIA) and University of Wisconsin, Madison (UW) the outcome has been more complex. While CR monkeys in the UW study...
Immaturity of cardiomyocytes derived from induced pluripotent stem cells is an important issue in the field of cell therapeutics. In article number 1707378, Morteza Mahmoudi and co‐workers develop substrates with multi‐scale topography resembling the three‐dimensional features of the native heart environment to address the issue of immaturity of ca...
Producing mature and functional cardiomyocytes (CMs) by in vitro differentiation of induced pluripotent stem cells (iPSCs) using only biochemical cues is challenging. To mimic the biophysical and biomechanical complexity of the native in vivo environment during the differentiation and maturation process, polydimethylsiloxane substrates with 3D topo...
Loss of cardiomyocytes is a major cause of heart failure, and while the adult heart has a limited capacity for cardiomyogenesis, little is known about what regulates this ability or whether it can be effectively harnessed. Here we show that 8 weeks of running exercise increase birth of new cardiomyocytes in adult mice (~4.6-fold). New cardiomyocyte...
Thioredoxin interacting protein (Txnip) was initially identified as a protein that can bind to and inhibit thioredoxin, but it is now recognized to participate in nutrient sensing and carbohydrate metabolism. We recently discovered that Txnip binds to the fructose transporters, Glut 2 and Glut 5, to increase the fructose uptake by enterocytes. Addi...
Background
-Defining conserved molecular pathways in animal models of successful cardiac regeneration could yield insight into why adult mammals have inadequate cardiac regeneration after injury. Insight into the transcriptomic landscape of early cardiac regeneration from model organisms will shed light on evolutionarily conserved pathways in succ...
Significance
GDF8 is a signaling protein that inhibits muscle mass. Inhibitors of GDF8 are highly sought as therapeutics for the treatment of muscle-wasting diseases. During synthesis, GDF8 is made as a precursor where the signaling segment is cleaved from the N-terminal prodomain, which remains associated and inhibits signaling. Activation involve...
The field of heart regeneration has witnessed significant advancements toward developing new therapeutics in the past decade. Strategies to regenerate the adult human heart are in constant development in both the experimental and clinical arenas. Although stem cell therapies remain controversial, cell-based heart repair is a promising approach towa...
The adult mammalian heart possesses only limited capacity for innate regeneration and the response to severe injury is dominated by the formation of scar tissue. Current therapy to replace damaged cardiac tissue is limited to cardiac transplantation and thus many patients suffer progressive decay in the heart’s pumping capacity to the point of hear...
Soluble IL-13 receptor alpha 1, or sIL13rα1, is a soluble protein that binds to Interleukin 13 (IL-13) and that has been previously described in mice. The function of sIL13rα1 remains unclear, but it has been hypothesized to act as a decoy receptor for IL-13. Recent studies have identified a role for IL-13 in glucose metabolism, suggesting that a d...
Genetic and functional analyses of 120 mouse strains have identified a heart regeneration candidate gene that modulates the contractile sarcomeric apparatus. This gene, Tnni3k, controls the frequency of the mononuclear, diploid cardiomyocyte population, which affects cardiomyocyte proliferative potential after injury.
Growth/differentiation factor 8 (GDF8) or myostatin negatively regulates muscle mass. GDF8 is held in a latent state through interactions with its N-terminal prodomain, much like TGF-β. Using a combination of small angle X-ray scattering and mutagenesis, we characterized the interactions of GDF8 with its prodomain. Our results show that the prodoma...
[This corrects the article DOI: 10.1371/journal.pone.0173823.].
Cell therapy is an exciting option for repairing the injured heart, one which has attracted considerable interest over the past 15 years. Consensus exists that the injection/infusion or tissue-based implantation of various cell types may exert therapeutic effects, and there is general agreement that additional molecular, translational and clinical...
Basal beige adipocyte gene expression in control and Arrdc3-null adipocytes.
Quantitative PCR analysis of gene expression in control versus adipocyte-specific Arrdc3-null cells. (n = 6,7).
(TIF)
Increased expression of Ucp1 in white adipose tissue of male adipocyte-specific Arrdc3-null mice.
A) Adipocyte-specific Arrdc3-null male mice and littermate controls were weighed for 16 weeks and no differences in body weight were found (n = 4–17). B) Quantitative PCR analysis of gene expression in subcutaneous adipose tissue. (n = 3) *p<0.05. C) W...
Adaptive thermogenesis and cold-induced activation of uncoupling protein 1 (Ucp1) in brown adipose tissue in rodents is well-described and attributed to sympathetic activation of β-adrenergic signaling. The arrestin domain containing protein Arrdc3 is a regulator of obesity in mice and also appears linked to obesity in humans. We generated a mouse...
Increased expression of Ucp1 in visceral adipose tissue of adipocyte-specific Arrdc3-null mice relative to controls.
Western analysis of Ucp1 protein expression in subcutaneous (SAT) and parametrial (VAT) adipose tissue.
(TIF)
Arrdc3 mRNA expression is lower in adipogenic treated SVF of adipocyte-specific Arrdc3-null mice.
Quantitative PCR analysis of Arrdc3 gene expression in control versus adipocyte-specific Arrdc3-null cells after adipogenic treatment. (n = 4).
(TIF)
Quantification of stable isotope tracers has revealed the dynamic state of living tissues. A new form of imaging mass spectrometry quantifies isotope ratios in domains much smaller than a cubic micron, enabling measurement of cell turnover and metabolism with stable isotope tracers at the single-cell level with a methodology we refer to as multi-is...
Background
Growth/differentiation factor 8 (GDF8) and GDF11 are two highly similar members of the transforming growth factor β (TGFβ) family. While GDF8 has been recognized as a negative regulator of muscle growth and differentiation, there are conflicting studies on the function of GDF11 and whether GDF11 has beneficial effects on age-related dysf...