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Basic science supporting cardiac regenerative medicine
Research Overview
Research Overview
Adult mammals, including humans and mice, cannot regenerate their hearts (Porrello and Olson, 2014). Ischemic injury after a heart attack causes permanent loss of cardiomyocytes leading to cardiac remodeling and disease. Zebrafish, on the other hand, possess a remarkable innate capacity for cardiac regeneration (Poss et al., 2002). After injury, adult zebrafish cardiomyocytes re-enter the cell-cycle and divide to replace lost cells (Kikuchi et al., 2010).
Adult mammals, including humans and mice, cannot regenerate their hearts (Porrello and Olson, 2014). Ischemic injury after a heart attack causes permanent loss of cardiomyocytes leading to cardiac remodeling and disease. Zebrafish, on the other hand, possess a remarkable innate capacity for cardiac regeneration (Poss et al., 2002). After injury, adult zebrafish cardiomyocytes re-enter the cell-cycle and divide to replace lost cells (Kikuchi et al., 2010).
Scientists have recently discovered that newborn mice have an amazing ability to regenerate their hearts, but this capacity is lost within the first week after birth (Porrello et al., 2011). Loss of heart regenerative potential in the neonates coincides with cardiomyocyte cell-cycle arrest and polyploidization (Soonpaa et al., 1996).
Scientists have recently discovered that newborn mice have an amazing ability to regenerate their hearts, but this capacity is lost within the first week after birth (Porrello et al., 2011). Loss of heart regenerative potential in the neonates coincides with cardiomyocyte cell-cycle arrest and polyploidization (Soonpaa et al., 1996).
We are interested in understanding the factors limiting cardiomyocyte proliferation in mammals to support efforts in cardiac regenerative medicine aimed at increasing the regenerative potential of the human heart.
We are interested in understanding the factors limiting cardiomyocyte proliferation in mammals to support efforts in cardiac regenerative medicine aimed at increasing the regenerative potential of the human heart.
Zebrafish (left) can naturally regenerate their hearts while mice (right) cannot.
Main Questions of Interest
Main Questions of Interest
1) What physiological triggers promote cardiomyocyte cell-cycle arrest and polyploidization?
1) What physiological triggers promote cardiomyocyte cell-cycle arrest and polyploidization?
2) What intrinsic molecular and cellular events influence cardiomyocyte cell-cycle resolution?
2) What intrinsic molecular and cellular events influence cardiomyocyte cell-cycle resolution?
3) How is cardiomyocyte cell-cycle regulated in polyploid cardiomyocytes?
3) How is cardiomyocyte cell-cycle regulated in polyploid cardiomyocytes?
Loss of Heart Regenerative Potential After Birth
Loss of Heart Regenerative Potential After Birth
Newborn mice can transiently regenerate their hearts during the first week after birth (Porrello et al., 2011). Lineage tracing experiments revealed that neonatal heart regeneration depends on the ability of cardiomyocytes to re-enter the cell-cycle after injury (Porrello et al., 2013) . However, mouse cardiomyocytes permanently exit the cell-cycle and undergo polyploidization during early postnatal development (Soonpaa et al., 1996). This transition coincides with the loss of heart regenerative capacity in these animals. Cardiomycyte proliferation in zebrafish, by comparison, is maintained even at adult stages (Poss et al., 2002). Our lab studies the physiological triggers that limit the ability of mammalian cardiomyocytes to divide and regenerate.
Newborn mice can transiently regenerate their hearts during the first week after birth (Porrello et al., 2011). Lineage tracing experiments revealed that neonatal heart regeneration depends on the ability of cardiomyocytes to re-enter the cell-cycle after injury (Porrello et al., 2013) . However, mouse cardiomyocytes permanently exit the cell-cycle and undergo polyploidization during early postnatal development (Soonpaa et al., 1996). This transition coincides with the loss of heart regenerative capacity in these animals. Cardiomycyte proliferation in zebrafish, by comparison, is maintained even at adult stages (Poss et al., 2002). Our lab studies the physiological triggers that limit the ability of mammalian cardiomyocytes to divide and regenerate.
Zebrafish maintain proliferative diploid cardiomyocytes throughout adulthood. Mouse cardiomyocytes exit the cell-cycle and undergo polyploidization shortly after birth. Diagrams produced with BioRender.com
Regulators of Cardiomyocyte Cell-cycle Entry and Resolution
Regulators of Cardiomyocyte Cell-cycle Entry and Resolution
Cardiomyocyte entry into the cell-cycle is complex and can result in several different outcomes including:
Cardiomyocyte entry into the cell-cycle is complex and can result in several different outcomes including:
1) Successful cell division resulting in two diploid mononucleated cardiomyocytes (generates new cells)
1) Successful cell division resulting in two diploid mononucleated cardiomyocytes (generates new cells)
2) Cytokinesis failure resulting in a cardiomyocyte with two diploid nuclei (no new cells generated)
2) Cytokinesis failure resulting in a cardiomyocyte with two diploid nuclei (no new cells generated)
3) Karyokinesis failure resulting in cardiomyocytes with a single tetraploid nuclei (no new cells generated)
3) Karyokinesis failure resulting in cardiomyocytes with a single tetraploid nuclei (no new cells generated)
Our lab seeks to define the molecular and cellular mechanisms influencing cardiomyocyte cell-cycle entry and resolution.
Our lab seeks to define the molecular and cellular mechanisms influencing cardiomyocyte cell-cycle entry and resolution.
Cardiomyocyte cell-cycle entry can resolve in various outcomes. Diagram produced with BioRender.com
Mechanisms of Cell-cycle Regulation in Polyploid Cardiomyocytes
Mechanisms of Cell-cycle Regulation in Polyploid Cardiomyocytes
The majority of cardiomyocytes in the hearts of most adult mammals are polyploid yet little is known about the proliferative potential of these cells. Our lab is characterizing cell-cycle dynamics in these cells.
The majority of cardiomyocytes in the hearts of most adult mammals are polyploid yet little is known about the proliferative potential of these cells. Our lab is characterizing cell-cycle dynamics in these cells.
The outcome of polyploid cardiomyocyte cell-cycle entry is less understood. Diagram produced with BioRender.com
Selected References:
Selected References:
Kikuchi, K., Holdway, J.E., Werdich, A.A., Anderson, R.M., Fang, Y., Egnaczyk, G.F., Evans, T., Macrae, C.A., Stainier, D.Y.R., and Poss, K.D. (2010). Primary contribution to zebrafish heart regeneration by gata4(+) cardiomyocytes. Nature 464, 601–605.
Porrello, E.R., and Olson, E.N. (2014). A neonatal blueprint for cardiac regeneration. Stem Cell Res. 13, 556–570.
Porrello, E.R., Mahmoud, A.I., Simpson, E., Hill, J.A., Richardson, J.A., Olson, E.N., and Sadek, H.A. (2011). Transient regenerative potential of the neonatal mouse heart. Science 331, 1078–1080.
Porrello, E.R., Mahmoud, A.I., Simpson, E., Johnson, B.A., Grinsfelder, D., Canseco, D., Mammen, P.P., Rothermel, B.A., Olson, E.N., and Sadek, H.A. (2013). Regulation of neonatal and adult mammalian heart regeneration by the miR-15 family. Proc. Natl. Acad. Sci. U. S. A. 110, 187–192.
Poss, K.D., Wilson, L.G., and Keating, M.T. (2002). Heart Regeneration in Zebrafish. Science 298, 2188–2190.
Soonpaa, M.H., Kim, K.K., Pajak, L., Franklin, M., and Field, L.J. (1996). Cardiomyocyte DNA synthesis and binucleation during murine development. Am. J. Physiol. 271, H2183-2189.
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