Kenneth R. Chien, MD, PhD

Director, MGH Cardiovascular Research Center
Department of Cell Biology, HMS
Harvard Stem Cell Institute
Massachusetts General Hospital
Richard B. Simches Research Center, CPZN 3208
185 Cambridge St.
Boston, MA 02114
Tel: (617) 643-3440
Fax: (617) 643-3451
Email:kchien@partners.org
Web Page: MGH Cardiovascular Research Center

The Chien lab focuses on the development of stem cell models of heart development and disease, based on the recent identification of novel mouse and human cardiac progenitor cells (Nature, 2005). Recently, in murine ES cells, they have discovered a single, master cardiovascular stem cell that can generate diverse endothelial/smooth muscle/cardiac lineages, a study which is now being extended into human ES cells. The type of current projects include:

Identifying specific cell markers

The first step in assessing the regenerative capacity of cardiac progenitor cells is to identify and unravel the nature of these cells. Focusing on recently identified cell groups, researchers are isolating the signals and steps in the development of a progenitor cell into a mature heart muscle cell. This process involves the use of tools and techniques such as transcriptional (signal) profiling and antibody generation. In addition, investigators are using colored tags to track the migration, incorporation, and function of these cells within the cardiovascular system.

In order to design effective cell replacement treatments, researchers must first learn how a normal cardiac progenitor cell develops into a mature heart muscle cell. Creating a genealogy tree (called a lineage map) will provide investigators with the pathways particular cells can take and indicate where they may degenerate. RNAi, chemical screening, and microarray analysis are some of the technologies used.

Developing disease-specific human ES cell lines

By using genetic engineering of human ES cell lines carrying specific genes responsible for heart disease, HSCI researchers will provide models with which to study certain properties of these cells. They will be able to study the phenomena of homing, asking whether stem cells migrate to the correct location (niche) within the body; of engraftment, seeking to learn if these cells establish themselves within that niche; of maturation, following the development of progenitor cells to maturity; and finally, of function, to learn if these mature cells behave like cardiac and vascular cells.

References:

• Knoll R, Hoshijima M, Hoffman HM, Person V, Lorenzen-Schmidt I, Bang ML, Hayashi T, Shiga N, Yasukawa H, Schaper W, McKenna W, Yokoyama M, Schork NJ, Omens JH, McCulloch AD, Kimura A, Gregorio CC, Poller W, Schaper J, Schultheiss HP, Chien KR. The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy. Cell. 2002 Dec 27;111(7):943-55.
• Pashmforoush M, Lu JT, Chen H, Amand TS, Kondo R, Pradervand S, Evans SM, Clark B, Feramisco JR, Giles W, Ho SY, Benson DW, Silberbach M, Shou W, Chien KR. Nkx2-5 pathways and congenital heart disease; loss of ventricular myocyte lineage specification leads to progressive cardiomyopathy and complete heart block. Cell. 2004 Apr 30;117(3):373-86.
• Laugwitz KL, Moretti A, Lam J, Gruber P, Chen Y, Woodard S, Lin LZ, Cai CL, Lu MM, Reth M, Platoshyn O, Yuan JX, Evans S, Chien KR. Postnatal isl1+ cardioblasts enter fully differentiated cardiomyocyte lineages. Nature. 2005 Feb 10;433(7026):647-53.