Review articleMatters of the heart: Cellular sex differences
Introduction
While sex differences in cardiovascular disease have long been documented, the basis for these observed differences in pathophysiology must be due, at least in part, to cellular sex differences. Cells in male and female hearts are inherently different and have acquired differences during puberty and adulthood that influence their function and complex interactions (Fig. 1). Research is beginning to address cellular sex in many organ systems, but this aspect of biology is relatively under-studied. Here, we discuss sexual dimorphisms in the many cell types of the heart. We use “sex” to describe biology, rather than “gender,” which describes behavior. Recent reports have shown sex differences in the cellular composition of male and female hearts, including subclusters of cell populations. These observations demonstrate the challenges of unraveling the causes of larger-scale sex differences including cardiovascular disease risk, progression, and outcome [1].
Variations of the extracellular microenvironment are both a cause and an effect of sexual dimorphisms in the heart. A milieu of circulating factors, including cytokines and hormones, also contribute to cellular sex differences. In turn, these factors influence inflammation and wound repair mechanisms in a sexually dimorphic manner [20,21]. Sexual dimorphisms in extracellular matrix (ECM) exist not only due to physical differences such as height and gender normative lifestyles, but hormones and chromosomal cellular sex influence composition and homeostatic mechanisms. As such, we discuss only the influence of sex on cell phenotypes, not gender, although we acknowledge the influence of gender on heart biology is worth studying [22,23]. In response to injury and age, resident cells contribute to largely irreversible pathological matrix remodeling, while pregnancy and exercise result in adaptive remodeling that is reversible [24]. Many of these sex differences can be linked to hormonal differences, as sex hormone receptors are known to mediate fibrotic-specific ECM pathways [25], yet chromosomal genotype and epigenetic regulation can also drive cellular sex differences.
Compared to myocytes, little is known about cellular sex differences in the non-myocytes of the heart. While cardiac myocytes constitute 70% of the mass of the heart, they constitute only about 30% of the cell number. In the fetal heart, cardiac myocytes constitute a higher fraction of cells, with the proportion declining during maturation due to the greater proliferation of cardiac non-myocytes. According to the heart cell atlas [26], the most abundant cell types in the adult human heart, in descending order are: cardiac myocytes, endothelial cells, pericytes, fibroblasts, myeloid cells, lymphoid cells, smooth muscle cells, and adipocytes (Fig. 2).
In this review article, we describe known sex differences in the cells of the mammalian heart, with an emphasis on non-myocytes. We discuss current literature regarding the extracellular and intracellular sex differences of each cell type. We briefly discuss cardiac myocytes and myeloid cells, as sex differences for both cell populations have been reviewed elsewhere [25,[27], [28], [29]]. There are fewer reports on cardiac smooth muscle cells, myeloid cells, and pericytes, but some seminal work is presented here. We also focus on cardiac fibroblasts, endothelial cells, and valve cells and present these cell populations in the most depth. Lymphoid cells, neural cells, and adipocytes are not discussed, as little is known about their sex differences, and they constitute small proportions of cells in the heart. We focus on baseline sex differences for each cell type, but also include findings on the dimorphic response of male and female cells to injury, age, and exercise as available. Cell types will be discussed in order of abundance in the heart. Many studies to date have made male and female comparisons for a single cell type; however, we acknowledge the complexities regarding cell-cell and cell-matrix interactions in the heart as a driving factor of sexually dimorphic phenotypes. To address these complexities, we conclude by discussing multicellular, bioengineering approaches that could direct future investigations of cellular sex in the heart and help develop in vitro models that could inform clinical studies.
Section snippets
Clinical/pathophysiology
Adult cardiac myocytes (CMs) produce contractile forces that pump blood through the body and constitute the majority of the cellular volume of the heart. Moreover, CM loss during cardiac injury is a major cause of heart failure since there is little proliferation of CMs post-natally [30]. Instead, there is replacement fibrosis, unlike pathological cardiac remodeling, where changes in the heart during pregnancy and exercise are largely due to CM enlargement and there are no indications of
Discussion and forward thinking
An increased focus on the pathophysiology of sex differences that arise in cardiac disease is a promising direction for improving patient health and treatment, yet more research is needed to understand the nuances that occur because of cellular sex, especially within individual cell types present in the heart. Based on the above-mentioned studies on cellular sex (SI Table 1), it is clear that research focused on understanding the mechanisms involved is needed if sex-dependent cardiac therapies
Conclusion
Sex differences in cardiac myocytes, fibroblasts, endothelial cells, valve cells, and other resident cells must drive the well-known pathophysiological differences between men and women. However, very little is known about the mechanisms underlying cellular sex phenotypes. Recent studies suggest there are differences between the sexes in cellularity, their response to extracellular cues, and gene expression and epigenetics that ultimately influence the pathophysiology of heart disease. In
Declaration of Competing Interest
The authors declare that they have no conflict of interest.
Acknowledgments
Authors acknowledge funding from NIH (RO1 HL132353, R01 HL142935, R01 GM29090, R01 117138). C.J.W. acknowledges funding from the NIH NRSA Predoctoral Fellowship (F31HL142223). M.E.S. acknowledges funding from the NIH (T32 HL007822). B.A.A. acknowledges funding from the NIH (K99 HL148542) and the Burroughs Welcome Fund Postdoctoral Enrichment Program. The graphical abstract and Fig. 1 were created using BioRender.com.
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