A framework for developing sex-specific engineered heart models.

Roberta Lock,Manuel Tamargo,Milica Radisic,Hadel Al Asafen,Gordana Vunjak-Novakovic,Yimu Zhao,Sharon Fleischer

doi:10.1038/s41578-021-00381-1

Roberta Lock, Manuel Tamargo + Show 5 more

Open Access

https://doi.org/10.1038/s41578-021-00381-1

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Abstract

The convergence of tissue engineering and patient-specific stem cell biology has enabled the engineering of in vitro tissue models that allow the study of patient-tailored treatment modalities. However, sex-related disparities in health and disease, from systemic hormonal influences to cellular-level differences, are often overlooked in stem cell biology, tissue engineering and preclinical screening. The cardiovascular system, in particular, shows considerable sex-related differences, which need to be considered in cardiac tissue engineering. In this Review, we analyse sex-related properties of the heart muscle in the context of health and disease, and discuss a framework for including sex-based differences in human cardiac tissue engineering. We highlight how sex-based features can be implemented at the cellular and tissue levels, and how sex-specific cardiac models could advance the study of cardiovascular diseases. Finally, we define design criteria for sex-specific cardiac tissue engineering and provide an outlook to future research possibilities beyond the cardiovascular system.

Highlights

Intrinsic differences in genome, Sex differences in gene expression and regulatory networks are present across multiple transcriptome and proteome human tissues[70,261] at birth40,41
Abstract | The convergence of tissue engineering and patient-specific stem cell biology has enabled the engineering of in vitro tissue models that allow the study of patient-tailored treatment modalities
In traditional cardiac tissue engineering approaches (Fig. 2), cardiomyocytes are cultured into large and elongated constructs expressing cardiac genes associated with contraction and calcium handling, displaying orderly ultrastructure and producing forces characteristic of a mature phenotype[13,14,15,16]

Summary

Donor cohort selection

2. Reprogrammed iPSC colonies expression of pluripotency transcription factors iPSCs (OCT3/4, SOX2, MYC). 3. iPSC-derived cardiac cell subtypes cardiomyocytes, cardiac fibroblasts and endothelial cells are differentiated. 4. Cells seeded into a biomaterial biomaterials (decellularized ECM from primary sources, natural or synthetic polymers). Synthetic polymers can be used for a hormone-responsive, primary sources to match sex-specific element-free

Patient-specific cardiac tissue model

Findings

Study design