Many approaches have been explored to regenerate the heart muscle followingischemic injury, out of which is the induction of cardiomyocytes proliferation. Ourprevious work demonstrated that cell-cycle was successfully induced incardiomyocytes by viral expression of combination of four cell-cycle factors: cyclinB1, CDK1, cyclin D1 and CDK4; termed as 4 factors (4F). However, only 15-20 % ofthe cells expressing the four factors progress into cell-cycle, while the remainderare quiescent. A pertinent question in the field of cardiac regeneration is why allviral or in vivo transgenic approaches to induce adult cardiomyocyte proliferation,e.g., 4F, YAP, and CyclinA2, promote proliferation in only a subset ofcardiomyocytes. This general finding suggests that factors or conditions beyondcell-cycle induction influence the probability and perpetuation of cardiomyocytedivision.Here we aim to investigate why only a subpopulation of cardiomyocytes is able toprogress through cell-cycle.Temporal single cell RNA sequencing of 60 days mature hiPS-CMs 24, 48 and 72hours post infection with 4F or control virus revealed that a unique population ofcardiomyocytes in the LacZ control group [1026 cells out of 6761 cells (~15%)] thatdisappears after treatment with 4F; another unique cluster with similar cellnumbers appears 24 h after 4F transduction (Cluster 3), which suggests that theinitial population was primed to proliferate. One of the major characteristics of thisprimed subpopulation is the expression of CD36, a major fatty acids transporter incardiomyocytes, and that 4F induction of cell-cycle completely abolishes CD36expression. knocking down CD36 in hiPS-CMs for 48 hours followed by induction ofproliferation using 4F led to 50-70% reduction in proliferation capacity of thecardiomyocytes compared to the control cells. Furthermore, cardiomyocytesisolated at P7 from CD36 knockout mice showed 30-40 % reduction incardiomyocytes proliferation capacity at baseline and after 4F induction ofproliferation compared to cardiomyocytes isolated from WT controls.These findings suggest that CD36 is needed to prime the CMs to proliferate, andthis can be, at least partially, through provision of energy requirements throughβ-oxidation of fatty acids.

Abstract P337: CD36 Is Required To Prime Cardiomyocytes For Proliferation

Abou Bakr Salama;Giovanni B Luciani
2021-01-01

Abstract

Many approaches have been explored to regenerate the heart muscle followingischemic injury, out of which is the induction of cardiomyocytes proliferation. Ourprevious work demonstrated that cell-cycle was successfully induced incardiomyocytes by viral expression of combination of four cell-cycle factors: cyclinB1, CDK1, cyclin D1 and CDK4; termed as 4 factors (4F). However, only 15-20 % ofthe cells expressing the four factors progress into cell-cycle, while the remainderare quiescent. A pertinent question in the field of cardiac regeneration is why allviral or in vivo transgenic approaches to induce adult cardiomyocyte proliferation,e.g., 4F, YAP, and CyclinA2, promote proliferation in only a subset ofcardiomyocytes. This general finding suggests that factors or conditions beyondcell-cycle induction influence the probability and perpetuation of cardiomyocytedivision.Here we aim to investigate why only a subpopulation of cardiomyocytes is able toprogress through cell-cycle.Temporal single cell RNA sequencing of 60 days mature hiPS-CMs 24, 48 and 72hours post infection with 4F or control virus revealed that a unique population ofcardiomyocytes in the LacZ control group [1026 cells out of 6761 cells (~15%)] thatdisappears after treatment with 4F; another unique cluster with similar cellnumbers appears 24 h after 4F transduction (Cluster 3), which suggests that theinitial population was primed to proliferate. One of the major characteristics of thisprimed subpopulation is the expression of CD36, a major fatty acids transporter incardiomyocytes, and that 4F induction of cell-cycle completely abolishes CD36expression. knocking down CD36 in hiPS-CMs for 48 hours followed by induction ofproliferation using 4F led to 50-70% reduction in proliferation capacity of thecardiomyocytes compared to the control cells. Furthermore, cardiomyocytesisolated at P7 from CD36 knockout mice showed 30-40 % reduction incardiomyocytes proliferation capacity at baseline and after 4F induction ofproliferation compared to cardiomyocytes isolated from WT controls.These findings suggest that CD36 is needed to prime the CMs to proliferate, andthis can be, at least partially, through provision of energy requirements throughβ-oxidation of fatty acids.
Cardiomyocytes proliferation, Membrane transporters
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11562/1082866
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