1. Evolutionary Biology
Download icon

Stem Cells: Getting to the heart of cardiovascular evolution in humans

  1. Alex Pollen  Is a corresponding author
  2. Bryan J Pavlovic
  1. University of California, San Francisco, United States
Insight
  • Cited 0
  • Views 1,022
  • Annotations
Cite this article as: eLife 2019;8:e47807 doi: 10.7554/eLife.47807
Voice your concerns about research culture and research communication: Have your say in our 7th annual survey.

Abstract

Differences in the response of cardiomyocytes to oxygen deprivation in humans and chimpanzees may explain why humans are more prone to certain heart diseases.

Main text

Cardiovascular disease is one of the leading causes of death in both humans and captive chimpanzees. However, despite having similar heart anatomies, humans and chimpanzees are prone to different types of cardiovascular disease. In humans, a build-up of fatty materials in the arteries (a condition called atherosclerosis) can restrict blood flow to the heart, which can cause myocardial ischemia. On the other hand, great apes, including chimpanzees, are more likely to suffer heart disease from myocardial fibrosis (Lowenstine et al., 2016). This condition, which rarely leads to heart disease in humans, involves increased deposition of collagen in heart tissue (Lammey et al., 2008).

Both genetic and environmental factors could be responsible for these differences. Interestingly, cholesterol is a major risk factor for atherosclerosis in humans, yet captive chimpanzees manage to avoid this condition despite having higher cholesterol levels than humans (Varki et al., 2009). However, a lack of appropriate model systems has made it difficult to investigate how genetic differences in disease susceptibility evolved between these two species.

Recent studies have shown that cardiomyocytes (heart muscle cells derived from stem cells) recapitulate many of the features of normal human and chimpanzee hearts, although there are important differences in metabolism and maturation state (Pavlovic et al., 2018). Since it is possible to grow human and chimpanzee cardiomyocytes under common environmental conditions, this provides an opportunity to study differences in the genetics of the two systems (Gallego Romero et al., 2015). Now, in eLife, Michelle Ward and Yoav Gilad from the University of Chicago report how cardiomyocytes can be used to compare the genomic consequences of myocardial ischemia in humans and chimpanzees (Ward and Gilad, 2019).

A characteristic symptom of myocardial ischemia is oxygen deprivation, also known as hypoxia, which is caused by a reduction in the flow of blood to the heart. To simulate hypoxia, Ward and Gilad first cultured cardiomyocytes in normal oxygen levels, then exposed them to a ten-fold decrease in oxygen for six hours, before returning them to normal oxygen levels. Depriving heart tissue of oxygen typically leads to increased production of reactive oxygen species (such as peroxides) that can cause DNA damage and lipid degradation. Hypoxia induced similar effects in both human and chimpanzee cardiomyocytes, suggesting that such experiments can recapitulate the effects of myocardial ischemia.

RNA sequencing revealed that nearly one third of the genes that are expressed in cardiomyocytes respond to hypoxia. Moreover, 75% of these responded in the same way in both species, suggesting that hypoxia has a widespread and largely conserved effect on gene expression. In contrast, previous work has shown that the immune responses in humans and chimpanzees are quite different (Barreiro et al., 2010).

Next, Ward and Gilad investigated how patterns of gene expression were influenced by hypoxia within these two species. Despite the similarities revealed in the RNA sequencing experiments, several hundred genes still differed in their responses. One possible explanation for these differences is that hypoxia-related transcription factors bind to response genes to varying degrees. Consistent with this possibility, hypoxia-related factors were shown to frequently bind to, or near to, conserved response genes, but not to genes with chimpanzee-specific responses. This suggests that changes in transcription factor binding, and possibly changes to the sites they bind to, may be responsible for the several hundred genes that respond differently to hypoxia in the two species.

Another notable difference is the response of a protein called RASD1, which is upregulated during hypoxia in human cardiomyocytes but not in chimpanzee cardiomyocytes. Interestingly, this gene is also upregulated in patients with myocardial ischemia and other diseases related to atherosclerosis. RASD1 could therefore have a role in regulating hypoxia-induced tissue damage in humans.

Ward and Gilad then explored the role of genes called eQTL genes (where eQTL is short for expression quantitative trait loci). Genetic variation within these genes can explain some of the disparity in mRNA levels among individuals in a population. Intersecting eQTL genes with genetic association studies has become a popular strategy for identifying disease-risk genes (Albert and Kruglyak, 2015). However, several recent lines of evidence suggest that eQTL genes may reflect mostly neutral genetic variation and are not therefore associated with any specific diseases (Jasinska et al., 2017; Tung et al., 2015).

Ward and Gilad found that there was a significant overlap between the conserved hypoxia response genes and the genes that are upregulated in patients with myocardial ischemia. This overlap indicates that the response genes are relevant to disease: however, the overlap between these genes and eQTL genes was lower than expected (Figure 1). Therefore, identifying the genetic variants and genes that influence disease-relevant responses, such as hypoxia, is likely to be more informative than traditional baseline eQTL studies. This means that stem cell models, such as those studied by Ward and Gilad, could be used more generally to study how common variation and evolved genetic differences influence other disease-relevant responses.

Using stem cell models to explore the genetic effects that influence susceptibility to cardiovascular disease.

Ward and Gilad explored the effects of hypoxia (that is, oxygen deprivation) on cardiomyocytes (heart cells derived from stem cells) from humans and chimpanzees. They found that 75% of the genes that respond to hypoxia respond in the same way in both species (third panel). They also observed a large overlap between these conserved response genes and genes that are upregulated in patients with ischemia (fourth panel; left), but little overlap with eQTL genes (right).

References

    1. Lammey ML
    2. Baskin GB
    3. Gigliotti AP
    4. Lee DR
    5. Ely JJ
    6. Sleeper MM
    (2008)
    Interstitial myocardial fibrosis in a captive chimpanzee (Pan troglodytes) population
    Comparative Medicine 58:389–394.

Article and author information

Author details

  1. Alex Pollen

    Alex Pollen is in the Department of Neurology, and The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, United States

    For correspondence
    Alex.Pollen@ucsf.edu
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3263-8634
  2. Bryan J Pavlovic

    Bryan J Pavlovic is in the Department of Neurology, and The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, United States

    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7751-5315

Publication history

  1. Version of Record published: May 28, 2019 (version 1)

Copyright

© 2019, Pollen and Pavlovic

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,022
    Page views
  • 79
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Evolutionary Biology
    Kai He et al.
    Research Article

    The speciose mammalian order Eulipotyphla (moles, shrews, hedgehogs, solenodons) combines an unusual diversity of semi-aquatic, semi-fossorial, and fossorial forms that arose from terrestrial forbearers. However, our understanding of the ecomorphological pathways leading to these lifestyles has been confounded by a fragmentary fossil record, unresolved phylogenetic relationships, and potential morphological convergence, calling for novel approaches. The net surface charge of the oxygen-storing muscle protein myoglobin (ZMb), which can be readily determined from its primary structure, provides an objective target to address this question due to mechanistic linkages with myoglobin concentration. Here we generate a comprehensive 71 species molecular phylogeny that resolves previously intractable intra-family relationships and then ancestrally reconstruct ZMb evolution to identify ancient lifestyle transitions based on protein sequence alone. Our phylogenetically informed analyses confidently resolve fossorial habits having evolved twice in talpid moles and reveal five independent secondary aquatic transitions in the order housing the world's smallest endothermic divers.

    1. Computational and Systems Biology
    2. Evolutionary Biology
    Alexander J Tarashansky et al.
    Research Advance

    Comparing single-cell transcriptomic atlases from diverse organisms can elucidate the origins of cellular diversity and assist the annotation of new cell atlases. Yet, comparison between distant relatives is hindered by complex gene histories and diversifications in expression programs. Previously, we introduced the self-assembling manifold (SAM) algorithm to robustly reconstruct manifolds from single-cell data (Tarashansky et al., 2019). Here, we build on SAM to map cell atlas manifolds across species. This new method, SAMap, identifies homologous cell types with shared expression programs across distant species within phyla, even in complex examples where homologous tissues emerge from distinct germ layers. SAMap also finds many genes with more similar expression to their paralogs than their orthologs, suggesting paralog substitution may be more common in evolution than previously appreciated. Lastly, comparing species across animal phyla, spanning mouse to sponge, reveals ancient contractile and stem cell families, which may have arisen early in animal evolution.