Deriving Cardiomyocytes from Human Amniocytes

Abstract

STATEMENTAmniocytes are a possible source of patient-specific cardiomyocytes for newborns with congenital heart disease. Genome-wide DNA methylation patterns and transcriptional repressors preclude direct differentiation, but pluripotent reprogramming provides cardiomyocytes for dissecting genetic pathways contributing to this disease. ABSTRACTMany forms of congenital heart disease (CHD) have high morbidity-mortality rates and require challenging surgeries. Human amniocytes have important stem cell characteristics and could potentially provide patient-specific tissue for repairs of some types of CHDs. We report that amniocytes express features of poised cardiomyocytes. However, a variety of direct reprogramming approaches failed to convert their fetal and transcriptionally repressed state into bona fide cardiomyocytes. Induced-pluripotent stem cell (iPSC) reprogramming removes repression and converts amniocytes to a baseline pluripotent state. Based on molecular and electrophysiological signatures, iPSC reprogrammed amniocytes can be induced to differentiate into functionally immature, predominantly ventricular cardiomyocytes and a heterogeneous mixture of vascular and unspecified epithelial cells. Developmental time course analyses and pattern clustering of amniocyte-derived cardiomyocytes identifies numerous temporal coregulators of cardiac induction and maturation as well as distinct sarcomeric and ion channel gene signatures. Normal fetal cardiomyocytes are derived by overcoming complex forms of transcriptional repression that suppress direct transdifferentiation of human amniocytes. These results suggest the possibility of using amniocytes as a source of patient-specific ventricular cardiomyocytes for cell therapies.

Amniotic Fluid Mesenchymal Stromal Cells Derived from Fetuses with Isolated Cardiac Defects Exhibit Decreased Proliferation and Cardiomyogenic Potential

“…It has been reported that amniotic epithelial cells contain progenitor cells or resident cardiac stem cells that differentiate into various organs such as the heart, brain, and kidney [ 16 ]. These resident cardiac stem cells in AF have been studied for the expression of transcription factors of mesodermal origin, such as NKx 2-5 , GATA-4 , and the TBX family, which play an essential role in heart development during embryogenesis [ 17 , 18 ]. Thus, any defects in the functional properties of these cardiac stem cells or cardiac progenitor stem cells will contribute to an increased risk of neonatal heart defects as in the case of ICHDs.…”