Ischemic survival and constitutively active autophagy in self-beating atypically-shaped cardiomyocytes (ACMs): characterization of a new subpopulation of heart cells

Abstract

Atypically-shaped cardiomyocytes (ACMs) are a new subpopulation of spontaneously beating heart cells with a peculiar morphology identified within a culture of cardiac myocyte-depleted fraction (CMDF) cells obtained from adult mouse heart. ACMs originate from small cells in CMDF and grow in size and start beating within ~3 days culture without appreciable proliferation or express stem cell marker proteins, but stay in the heart until elderly stages. However, the characteristics of ACMs are largely unclear. The present study examined whether pre-exposure of CMDF cells to severe ischemia abolished the ability of ACMs to develop into beating cells. Of ACMs that underwent ischemia, ~50 % grew in size, changed the morphology, and started beating during the subsequent culture under normoxia. ACMs displayed constitutively active autophagy during the culture. The results suggest the possibility that the development of beating ACMs could occur in injured heart, even if the surviving cell population is small.

Identification of cardiac progenitors that survive in the ischemic human heart after ventricular myocyte death

“…1c). No viable ventricular myocytes were detected, even in independent cultures, over these 6 days of culture14. Instead, fibroblast-like cells originating from the endogenous heart tissue, such as cardiac fibroblasts or dedifferentiated cardiomyocytes2122, proliferated, becoming nearly confluent after culture for 20 days (Fig.…”

“…Atypically-shaped cardiomyocytes (ACMs) are a type of cardiac progenitors identified in the cultures of cardiomyocyte-removed fraction obtained from mouse cardiac ventricles that spontaneously develop into beating cells within 3–5 days culture121314. Beating ACMs possess a peculiar morphology far different from a typical cardiomyocytes and the electrophysiological properties similar to those of sino-atrial (SA) nodal pace maker cells12.…”

“…Beating ACMs possess a peculiar morphology far different from a typical cardiomyocytes and the electrophysiological properties similar to those of sino-atrial (SA) nodal pace maker cells12. ACMs can be obtained from neonatal to aged heart, while preserving the expression of the fetal cardiac gene products, such as atrial natriuretic peptide (ANP) and T-type Ca 2+ channel Ca V 3.213, and are more ischemic resistant compared with the ventricular myocytes14. ACMs are thus thought to be not classified into stem cells but some kinds of cardiac progenitors that already entered into a cardiomyocyte lineage.…”

Therapeutic targeting of autophagy in myocardial infarction and heart failure

“…Moreover, a recent report described a population of heart cells with a morphology that differs from cardiomyocytes (hence the name "atypically-shaped cardiomyocytes (ACMs)"). These cells are particularly resistant to ischemic conditions and spontaneously develop into beating cardiomyocytes, suggesting the existence of residual fetal heart cells in the adult murine heart [82]. Non-the-less, the regenerative potential of the adult mammalian heart is extremely limited.…”

“…Likewise, inducing autophagy in bone marrow-derived mesenchymal stem cells has been proposed as an approach to increase their viability upon transplantation, and hence their therapeutic efficiency in infarcted hearts [95,96]. Interestingly, the ACMs described by Omatsu et al were also reported to have numerous autophagosomes, and their ability to develop in vitro was shown to be sensitive to pharmacological inhibition of autophagy [82]. Furthermore, autophagy has been shown to be required for both the maintenance of stem cell pools in several tissues [89,[97][98][99].…”