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A Comparative Assessment of iPSC Derived Cardiomyocytes with Heart Tissues in Humans and Chimpanzees

ABSTRACT: To study regulatory differences between species, the field of comparative primate genomics has used several approaches, including the use of post mortem frozen tissues, cell lines, and model organisms. However, there are limited quality cell lines from primates and post-mortem tissues cannot be staged, are not amenable to experimental perturbations and are often subject to high environmental variances. Inducible pluripotent stem cells (iPSCs) are an attractive system to study primate biology in a comparative context. However, the fidelity of iPSC derived cell types to primary tissues needs to be assayed in a comparative primate context before the utility of iPSCs can be fully realized for comparative genomics. In order to comprehensively benchmark the performance of iPSC model systems in a comparative framework, we collected RNA-sequencing from primary adult heart tissue and iPSC derived cardiomyocytes from multiple human and chimpanzee individuals. We identified the optimal parameters of iPSC differentiation into cardiomyocytes that minimized differences between each species and their respective adult tissue counterparts in a balanced manner across species. We found that iPSC derived cardiomyocytes are able to recapitulate 50% of the interspecies gene expression differences identified between human and chimpanzee in primary post mortem heart tissues. Furthermore, we determined that cultured cardiomyocytes appear more similar to adult hearts than any other single tissue in their ability to recapitulate differences in gene regulation between human and chimpanzee.

ORGANISM(S): Pan troglodytes Homo sapiens

PROVIDER: GSE110471 | GEO | 2018/08/08

REPOSITORIES: GEO

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Project description:Understanding cellular and molecular differences between human and non-human primates (NHPs) is essential to the basic comprehension of the evolution and diversity of our own species. Until now, preserved tissues have been the main source of most comparative studies between humans, chimpanzees (Pan troglodytes) and bonobos (Pan paniscus). However, these tissue samples do not fairly represent the distinctive traits of live cell behavior, are not amenable to genetic manipulation and do not allow translation of observed differences into phenotypical divergence. We hypothesized that induced pluripotent stem cells (iPSCs) could provide a unique biological resource to elucidate relevant phenotypical differences between human and the great apes and that those differences could have potential adaptation and speciation value. Here, we describe the generation and initial characterization of iPSCs from chimpanzees and bonobos as novel tools to explore our most recent evolution. Comparative gene expression analysis of human and NHP iPSCs revealed differences in regulation of Long Interspersed Nuclear Element (LINE-1 or L1) transposons. A force of change in mammalian evolution, L1 elements are retrotransposons that have remained active during primate evolution. We observed decreased levels of L1 restricting factors APOBEC3B (A3B)7 and PIWIL28 in NHP iPSCs which was correlated with increased human and chimpanzee L1 mobility and endogenous L1 mRNA levels. Moreover, results from manipulation of A3B and PIWIL2 levels in iPSCs suggested a causal inverse relationship between levels of these proteins and L1 activity. Finally, we found increased copy numbers of species-specific L1 elements in the genome of chimpanzees compared to humans, supporting the idea that increased L1 mobility in NHPs is not limited to iPSCs in culture and may have also occurred in the germline during primate evolution. We propose that differences in L1 mobility may have differentially shaped the genomes of humans and NHPs and could have had an adaptive significance. polyA RNA-Seq profiling of iPS cells from human, chimpanzee, and bonobo, and small RNA-Seq profiling of human iPS cells.

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A Comparative Assessment of iPSC Derived Cardiomyocytes with Heart Tissues in Humans and Chimpanzees

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