Publications by authors named "Sarah A Dick"

12 Publications

  • Page 1 of 1

Radiation Impacts Early Atherosclerosis by Suppressing Intimal LDL Accumulation.

Circ Res 2021 Feb 5;128(4):530-543. Epub 2021 Jan 5.

Toronto General Hospital Research Institute (J.I., C.A.S., S.J.H., M.G.A., J.A., S.A.D., T.E., J.M., N.I., H.M.I., C.K.P., X.G., K.T., J.J.-B., S.E., C.S.R., S.A.M., M.I.C.), University Health Network, Toronto, Canada.

Rationale: Bone marrow transplantation (BMT) is used frequently to study the role of hematopoietic cells in atherosclerosis, but aortic arch lesions are smaller in mice after BMT.

Objective: To identify the earliest stage of atherosclerosis inhibited by BMT and elucidate potential mechanisms.

Methods And Results: mice underwent total body γ-irradiation, bone marrow reconstitution, and 6-week recovery. Atherosclerosis was studied in the ascending aortic arch and compared with mice without BMT. In BMT mice, neutral lipid and myeloid cell topography were lower in lesions after feeding a cholesterol-rich diet for 3, 6, and 12 weeks. Lesion coalescence and height were suppressed dramatically in mice post-BMT, whereas lateral growth was inhibited minimally. Targeted radiation to the upper thorax alone reproduced the BMT phenotype. Classical monocyte recruitment, intimal myeloid cell proliferation, and apoptosis did not account for the post-BMT phenotype. Neutral lipid accumulation was reduced in 5-day lesions, thus we developed quantitative assays for LDL (low-density lipoprotein) accumulation and paracellular leakage using DiI-labeled human LDL and rhodamine B-labeled 70 kD dextran. LDL accumulation was dramatically higher in the intima of relative to mice, and was inhibited by injection of HDL mimics, suggesting a regulated process. LDL, but not dextran, accumulation was lower in mice post-BMT both at baseline and in 5-day lesions. Since the transcript abundance of molecules implicated in LDL transcytosis was not significantly different in the post-BMT intima, transcriptomics from whole aortic arch intima, and at single-cell resolution, was performed to give insights into pathways modulated by BMT.

Conclusions: Radiation exposure inhibits LDL entry into the aortic intima at baseline and the earliest stages of atherosclerosis. Single-cell transcriptomic analysis suggests that LDL uptake by endothelial cells is diverted to lysosomal degradation and reverse cholesterol transport pathways. This reduces intimal accumulation of lipid and impacts lesion initiation and growth.
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http://dx.doi.org/10.1161/CIRCRESAHA.119.316539DOI Listing
February 2021

Using High-Dimensional Approaches to Probe Monocytes and Macrophages in Cardiovascular Disease.

Front Immunol 2019 12;10:2146. Epub 2019 Sep 12.

University Health Network, Toronto General Research Institute, Toronto, ON, Canada.

High dimensional approaches that characterize single cells at unprecedented depth have helped uncover unappreciated heterogeneity, a better understanding of myeloid cell origins, developmental relationships and functions. These advancements are particularly important in cardiovascular disease, which remains the leading cause of death worldwide. Gradual, monocyte-dependent inflammatory processes, such as the development of atherosclerotic plaque within arterial vessels, contrasts with the robust acute response within the myocardium that occurs when a vessel is occluded. Monocytes and macrophages differentially contribute to tissue injury, repair and regeneration in these contexts, yet many questions remain about which myeloid cell types are involved in a coordinated, organ-level sterile inflammatory response. Single cell RNA sequencing, combined with functional analyses have demonstrated that at least three populations of resident cardiac macrophages exist, and after tissue injury, there is significant diversification of the tissue macrophage pool driven by recruited monocytes. While these studies have provided important insights, they raise many new questions and avenues for future exploration. For example, how do transcriptionally defined sub-populations of cardiac macrophages relate to each other? Are they different activation states along a pre-defined trajectory of macrophage differentiation or do local microenvironments drive newly recruited monocytes into distinct functions? The answers to these questions will require integration of high-dimensional approaches into biologically relevant experimental systems to ensure the predicted heterogeneity possess a functional outcome.
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http://dx.doi.org/10.3389/fimmu.2019.02146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6751379PMC
October 2020

Publisher Correction: Self-renewing resident cardiac macrophages limit adverse remodeling following myocardial infarction.

Nat Immunol 2019 May;20(5):664

Toronto General Hospital Research Institute, University Health Network (UHN), Toronto, Canada.

In the version of this article initially published, the equal contribution of the third author was omitted. The footnote links for that author should be "Sara Nejat" and the correct statement is as follows: "These authors contributed equally: Sarah A. Dick, Jillian A. Macklin, Sara Nejat." The error has been corrected in the HTML and PDF versions of the article.
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http://dx.doi.org/10.1038/s41590-019-0363-8DOI Listing
May 2019

Self-renewing resident cardiac macrophages limit adverse remodeling following myocardial infarction.

Nat Immunol 2019 01 11;20(1):29-39. Epub 2018 Dec 11.

Toronto General Hospital Research Institute, University Health Network (UHN), Toronto, Canada.

Macrophages promote both injury and repair after myocardial infarction, but discriminating functions within mixed populations remains challenging. Here we used fate mapping, parabiosis and single-cell transcriptomics to demonstrate that at steady state, TIMD4LYVE1MHC-IICCR2 resident cardiac macrophages self-renew with negligible blood monocyte input. Monocytes partially replaced resident TIMD4LYVE1MHC-IICCR2 macrophages and fully replaced TIMD4LYVE1MHC-IICCR2 macrophages, revealing a hierarchy of monocyte contribution to functionally distinct macrophage subsets. Ischemic injury reduced TIMD4 and TIMD4 resident macrophage abundance, whereas CCR2 monocyte-derived macrophages adopted multiple cell fates within infarcted tissue, including those nearly indistinguishable from resident macrophages. Recruited macrophages did not express TIMD4, highlighting the ability of TIMD4 to track a subset of resident macrophages in the absence of fate mapping. Despite this similarity, inducible depletion of resident macrophages using a Cx3cr1-based system led to impaired cardiac function and promoted adverse remodeling primarily within the peri-infarct zone, revealing a nonredundant, cardioprotective role of resident cardiac macrophages.
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http://dx.doi.org/10.1038/s41590-018-0272-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6565365PMC
January 2019

Expression of murine muscle-enriched A-type lamin-interacting protein (MLIP) is regulated by tissue-specific alternative transcription start sites.

J Biol Chem 2018 12 2;293(51):19761-19770. Epub 2018 Nov 2.

From the University of Ottawa Heart Institute, Ottawa, Ontario K1Y 4W7, Canada,

Muscle-enriched lamin-interacting protein () is an alternatively spliced gene whose splicing specificity is dictated by tissue type. MLIP is most abundantly expressed in brain, cardiac, and skeletal muscle. In the present study, we systematically mapped the transcriptional start and stop sites of murine Rapid amplification of cDNA ends (RACE) of transcripts from the brain, heart, and skeletal muscle revealed two transcriptional start sites (TSSs), exon 1a and exon 1b, and only one transcriptional termination site. RT-PCR analysis of the usage of the two identified TSSs revealed that the heart utilizes only exon 1a for MLIP expression, whereas the brain exclusively uses exon 1b TSS. Loss of exon 1a in mice resulted in a 7-fold increase in the prevalence of centralized nuclei in muscle fibers with the exon1a-deficient satellite cells on single fibers exhibiting a significant delay in commitment to a MYOD-positive phenotype. Furthermore, we demonstrate that the A-type lamin-binding domain in MLIP is encoded in exon 1a, indicating that MLIP isoforms generated with exon 1b TSS lack the A-type lamin-binding domain. Collectively these findings suggest that tissue-specific expression and alternative splicing play a critical role in determining MLIP's functions in mice.
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http://dx.doi.org/10.1074/jbc.RA118.003758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314141PMC
December 2018

A CD103 Conventional Dendritic Cell Surveillance System Prevents Development of Overt Heart Failure during Subclinical Viral Myocarditis.

Immunity 2017 11;47(5):974-989.e8

Toronto General Hospital Research Institute, University Health Network (UHN), Toronto ON, M5G 1L7, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto ON, M5S 1A1, Canada; Department of Immunology, University of Toronto, Toronto ON, M5S 1A1, Canada; Peter Munk Cardiac Centre, Toronto ON, M5G 1L7, Canada; Ted Rogers Centre for Heart Research, Toronto ON, M5G 1L7, Canada. Electronic address:

Innate and adaptive immune cells modulate heart failure pathogenesis during viral myocarditis, yet their identities and functions remain poorly defined. We utilized a combination of genetic fate mapping, parabiotic, transcriptional, and functional analyses and demonstrated that the heart contained two major conventional dendritic cell (cDC) subsets, CD103 and CD11b, which differentially relied on local proliferation and precursor recruitment to maintain their tissue residency. Following viral infection of the myocardium, cDCs accumulated in the heart coincident with monocyte infiltration and loss of resident reparative embryonic-derived cardiac macrophages. cDC depletion abrogated antigen-specific CD8 T cell proliferative expansion, transforming subclinical cardiac injury to overt heart failure. These effects were mediated by CD103 cDCs, which are dependent on the transcription factor BATF3 for their development. Collectively, our findings identified resident cardiac cDC subsets, defined their origins, and revealed an essential role for CD103 cDCs in antigen-specific T cell responses during subclinical viral myocarditis.
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http://dx.doi.org/10.1016/j.immuni.2017.10.011DOI Listing
November 2017

Chronic Heart Failure and Inflammation: What Do We Really Know?

Circ Res 2016 06;119(1):159-76

From the Division of Cardiology, Department of Medicine, University Health Network, Toronto, Ontario, Canada (S.A.D, S.E.); University of Toronto, Toronto, Ontario, Canada (S.E); Peter Munk Cardiac Centre, Toronto, Ontario, Canada (S.A.D, S.E.); and Toronto General Hospital Research Institute, Toronto, Ontario, Canada (S.A.D, S.E.).

As a greater proportion of patients survive their initial cardiac insult, medical systems worldwide are being faced with an ever-growing need to understand the mechanisms behind the pathogenesis of chronic heart failure (HF). There is a wealth of information about the role of inflammatory cells and pathways during acute injury and the reparative processes that are subsequently activated. We discuss the different causes that lead to chronic HF development and how the sum of initial inflammatory and reparative responses only sets the trajectory for disease progression. Unfortunately, comparatively little is known about the contribution of the immune system once the trajectory has been set, and chronic HF has been established-which clinically represents the majority of patients. It is known that chronic HF is associated with circulating inflammatory cytokines that can predict clinical outcomes, yet the causative role inflammation plays in disease progression is not well defined, and the majority of clinical trials that target aspects of inflammation in patients with chronic HF have largely been negative. This review will present what is currently known about inflammation in chronic HF in both humans and animal models as a means to highlight the gap in our knowledge base that requires further examination.
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http://dx.doi.org/10.1161/CIRCRESAHA.116.308030DOI Listing
June 2016

Caspase 3 cleavage of Pax7 inhibits self-renewal of satellite cells.

Proc Natl Acad Sci U S A 2015 Sep 8;112(38):E5246-52. Epub 2015 Sep 8.

Regenerative Medicine Program, Sprott Center for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada K1H 8L6; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada K1H 8L6; Department of Medicine, University of Ottawa, Ottawa, ON, Canada K1H 8L6

Compensatory growth and regeneration of skeletal muscle is dependent on the resident stem cell population, satellite cells (SCs). Self-renewal and maintenance of the SC niche is coordinated by the paired-box transcription factor Pax7, and yet continued expression of this protein inhibits the myoblast differentiation program. As such, the reduction or removal of Pax7 may denote a key prerequisite for SCs to abandon self-renewal and acquire differentiation competence. Here, we identify caspase 3 cleavage inactivation of Pax7 as a crucial step for terminating the self-renewal process. Inhibition of caspase 3 results in elevated Pax7 protein and SC self-renewal, whereas caspase activation leads to Pax7 cleavage and initiation of the myogenic differentiation program. Moreover, in vivo inhibition of caspase 3 activity leads to a profound disruption in skeletal muscle regeneration with an accumulation of SCs within the niche. We have also noted that casein kinase 2 (CK2)-directed phosphorylation of Pax7 attenuates caspase-directed cleavage. Together, these results demonstrate that SC fate is dependent on opposing posttranslational modifications of the Pax7 protein.
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http://dx.doi.org/10.1073/pnas.1512869112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4586827PMC
September 2015

Wnt/β-catenin controls follistatin signalling to regulate satellite cell myogenic potential.

Skelet Muscle 2015 28;5:14. Epub 2015 Apr 28.

Regenerative Medicine Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON K1H 8L6 Canada.

Background: Adult skeletal muscle regeneration is a highly orchestrated process involving the activation and proliferation of satellite cells, an adult skeletal muscle stem cell. Activated satellite cells generate a transient amplifying progenitor pool of myoblasts that commit to differentiation and fuse into multinucleated myotubes. During regeneration, canonical Wnt signalling is activated and has been implicated in regulating myogenic lineage progression and terminal differentiation.

Methods: Here, we have undertaken a gene expression analysis of committed satellite cell-derived myoblasts to examine their ability to respond to canonical Wnt/β-catenin signalling.

Results: We found that activation of canonical Wnt signalling induces follistatin expression in myoblasts and promotes myoblast fusion in a follistatin-dependent manner. In growth conditions, canonical Wnt/β-catenin signalling prime myoblasts for myogenic differentiation by stimulating myogenin and follistatin expression. We further found that myogenin binds elements in the follistatin promoter and thus acts downstream of myogenin during differentiation. Finally, ectopic activation of canonical Wnt signalling in vivo promoted premature differentiation during muscle regeneration following acute injury.

Conclusions: Together, these data reveal a novel mechanism by which myogenin mediates the canonical Wnt/β-catenin-dependent activation of follistatin and induction of the myogenic differentiation process.
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http://dx.doi.org/10.1186/s13395-015-0038-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4421991PMC
May 2015

Intrinsic-mediated caspase activation is essential for cardiomyocyte hypertrophy.

Proc Natl Acad Sci U S A 2013 Oct 7;110(43):E4079-87. Epub 2013 Oct 7.

Ottawa Hospital Research Institute, Sprott Centre for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital, Ottawa, ON, Canada K1H 8L6.

Cardiomyocyte hypertrophy is the cellular response that mediates pathologic enlargement of the heart. This maladaptation is also characterized by cell behaviors that are typically associated with apoptosis, including cytoskeletal reorganization and disassembly, altered nuclear morphology, and enhanced protein synthesis/translation. Here, we investigated the requirement of apoptotic caspase pathways in mediating cardiomyocyte hypertrophy. Cardiomyocytes treated with hypertrophy agonists displayed rapid and transient activation of the intrinsic-mediated cell death pathway, characterized by elevated levels of caspase 9, followed by caspase 3 protease activity. Disruption of the intrinsic cell death pathway at multiple junctures led to a significant inhibition of cardiomyocyte hypertrophy during agonist stimulation, with a corresponding reduction in the expression of known hypertrophic markers (atrial natriuretic peptide) and transcription factor activity [myocyte enhancer factor-2, nuclear factor kappa B (NF-κB)]. Similarly, in vivo attenuation of caspase activity via adenoviral expression of the biologic effector caspase inhibitor p35 blunted cardiomyocyte hypertrophy in response to agonist stimulation. Treatment of cardiomyocytes with procaspase 3 activating compound 1, a small-molecule activator of caspase 3, resulted in a robust induction of the hypertrophy response in the absence of any agonist stimulation. These results suggest that caspase-dependent signaling is necessary and sufficient to promote cardiomyocyte hypertrophy. These results also confirm that cell death signal pathways behave as active remodeling agents in cardiomyocytes, independent of inducing an apoptosis response.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3808644PMC
http://dx.doi.org/10.1073/pnas.1315587110DOI Listing
October 2013

Cell death proteins: an evolutionary role in cellular adaptation before the advent of apoptosis.

Bioessays 2013 Nov 14;35(11):974-83. Epub 2013 Aug 14.

Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.

Programmed cell death (PCD) or apoptosis is a broadly conserved phenomenon in metazoans, whereby activation of canonical signal pathways induces an ordered dismantling and death of a cell. Paradoxically, the constituent proteins and pathways of PCD (most notably the metacaspase/caspase protease mediated signal pathways) have been demonstrated to retain non-death functions across all phyla including yeast, nematodes, drosophila, and mammals. The ancient conservation of both death and non-death functions of PCD proteins raises an interesting evolutionary conundrum: was the primordial intent of these factors to induce cell death or to regulate other cellular adaptations? Here, we propose the hypothesis that apoptotic behavior of PCD proteins evolved or were co-opted from core non-death functions.
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http://dx.doi.org/10.1002/bies.201300052DOI Listing
November 2013

CD34 promotes satellite cell motility and entry into proliferation to facilitate efficient skeletal muscle regeneration.

Stem Cells 2011 Dec;29(12):2030-41

Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.

Expression of the cell surface sialomucin CD34 is common to many adult stem cell types, including muscle satellite cells. However, no clear stem cell or regeneration-related phenotype has ever been reported in mice lacking CD34, and its function on these cells remains poorly understood. Here, we assess the functional role of CD34 on satellite cell-mediated muscle regeneration. We show that Cd34(-/-) mice, which have no obvious developmental phenotype, display a defect in muscle regeneration when challenged with either acute or chronic muscle injury. This regenerative defect is caused by impaired entry into proliferation and delayed myogenic progression. Consistent with the reported antiadhesive function of CD34, knockout satellite cells also show decreased motility along their host myofiber. Altogether, our results identify a role for CD34 in the poorly understood early steps of satellite cell activation and provide the first evidence that beyond being a stem cell marker, CD34 may play an important function in modulating stem cell activity.
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http://dx.doi.org/10.1002/stem.759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3638793PMC
December 2011