Cardiac Myogenesis, Death and Regeneration

Professor Michael Schneider, Head of Group

Professor Schneider's research concerns the problem of cardiac muscle cell number, in its fundamental and applied dimensions. The capacity of mammals' heart tissue to undergo self-repair is quite meagre by comparison to newts or certain fish, virtually thwarting functional recovery from heart attacks and other forms of human heart disease.

Consequently, one theme in Professor Schneider's lab has been to dissect genetic circuits that impose the irreversible block to cell cycling in “post-mitotic” ventricular muscle. By developing Cre/lox systems that delete genes exclusively in cardiomyocytes, he was able to prove that growth arrest in cardiac muscle specifically required the “pocket protein” Rb, acting in concert with the related protein p130.

A second aspect concerns the drivers of cardiac muscle cell formation in the embryo, such as the Wnt and bone morphogenetic protein families and their downstream effectors. Using genome-wide expression profiling and RNA interference, Professor Schneider demonstrated in mouse embryonic stem cells an essential role for Sox17 in cardiac myogenesis driven by these signals. Sox17 acts largely by controlling Hex, a transcription factor required for endodermal cells to make the heart-inducing factors that pattern primitive mesoderm.

Third, an inverse approach to rescuing cardiac muscle cell number is to alleviate cell death. Professor Schneider showed that forced expression of Bcl-2 or telomerase reverse transcriptase in mouse myocardium reduces infarct size. These are good days to have a heart attack, if you are a mouse.

Fourth, he has identified multiple protein kinases that are activated by cardiac stress pathways, promote cardiac myocyte apoptosis, and are potential nodal control points for cardiac cell death.

In short, the goal is not just fundamental discoveries in cardiac biology, but also their conversion, over time, into testable theories of cardiac pathogenesis and workable therapies. Basic research projects are available for the many proteins studied (Cdk9, Cdk7, MAT1, TAK1, MAP4K4, Sox17, Hhex). Basic and applied projects are available on heart-derived progenitor cells for cardiac repair, directed differentiation, and cardiomyocyte apoptosis as therapeutic targets. 

Selected Publications

Liu Y; Asakura M; Inoue H; Nakamura T; Sano M; Niu Z; Chen M; Schwartz RJ; et al. (6 Mar 2007). Sox17 is essential for the specification of cardiac mesoderm in embryonic stem cells. Proc Natl Acad Sci U S A. 104:3859-3864.

Xie M; Zhang D; Dyck JR; Li Y; Zhang H; Morishima M; Mann DL; Taffet GE; et al. (14 Nov 2006). A pivotal role for endogenous TGF-beta-activated kinase-1 in the LKB1/AMP-activated protein kinase energy-sensor pathway. Proc Natl Acad Sci U S A. 103:17378-17383.

Oh H; Bradfute SB; Gallardo TD; Nakamura T; Gaussin V; Mishina Y; Pocius J; Michael LH; et al. (14 Oct 2003). Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction. Proc Natl Acad Sci U S A. 100:12313-12318.