Kenneth Bloch, MD

The mammalian heart is formed from distinct sets of first (FHF) and second (SHF) heart field progenitors. Although multipotent progenitors have been previously shown to give rise to cardiomyocytes, smooth muscle, and endothelial cells, the mechanism governing the generation of large numbers of differentiated progeny remains poorly understood. 
We have employed a two-colored fluorescent reporter system to isolate FHF and SHF progenitors from developing mouse embryos and embryonic stem cells.  Genome wide profiling of coding and non-coding transcripts revealed distinct molecular signatures of these progenitor populations.

Genetic modification of the mouse embryo allowed for the color-coding of different cardiac progenitors within the developing heart with green (left ventricle (LV) and inflow tract (IT)), red (pharyngeal mesoderm (PM)), or both green and red (shown in yellow, right ventricle (RV)).

We further identify a committed ventricular progenitor cell in the Islet 1 lineage that is capable of in vitro expansion, differentiation, and assembly into functional ventricular muscle tissue. These results represent a novel approach combining tissue-engineering with stem cell biology for the generation of functional ventricular tissue. In collaboration with Dr. Kevin K. Parker’s group at the Harvard School of Engineering and Applied Sciences, we employed these committed ventricular progenitors to engineer 2-dimensional cardiac tissue into a muscular thin film (MTF). The MTF beat spontaneously at a rate of approximately 20 contractions per minute and could be paced by field stimulation at 0.5 and 1.0 Hz.  To measure contractility, the MTF was fixed as a cantilever on one end and the contracting cardiomyocytes bent the MTF towards the cell-side during.  During diastole, the elastic PDMS film provided the antagonistic force that returned the MTF back to the relaxed position. The change in radius of curvature is inversely proportional to cardiomyocyte stress generation and is measured at ~5 kPa for the progenitor-derived cardiac tissue at peak systole, similar to MTFs engineered from neonatal rat ventricular cardiomyocytes.

The development of an in vivo multicolor reporter system in embryos and corresponding ES cell lines has now allowed for the purification of distinct subsets of heart field progenitors from the earliest stages of cardiogenesis. While Islet-1 primarily marks the SHF there have been no distinct markers for the FHF lineages that contribute to the left ventricle. The transcriptional profiles of the FHF and SHF lineages (including the expression of unique subsets of microRNAs) are sufficiently distinct to suggest that they have non-overlapping identities and the identification of independent FHF markers will now allow us to rigorously analyze their role in development and disease. 

A critical step in cardiogenesis is the formation and expansion of the ventricular myocyte lineage necessary for normal cardiac contractile function.  The discovery and purification from embryos and corresponding ESC lines of committed ventricular progenitors (CVPs) uncovers a novel mechanistic pathway for organogenesis through the expansion and assembly of CVPs into fully functional ventricular muscle tissue.   Thus, directed differentiation from multipotent islet progenitors to a specific differentiated progeny occurs via the formation of transient committed intermediate progenitors that are destined to become specific cell types.

In recent work, we have now also adopted a similar multi-color labeling scheme to isolate distinct subsets of cardiac progenitors from human ESC and human iPS cells.  In particular we have collected skin biopsies from patient with hypertrophic cardiomyopathy and are using this material for the isolation and characterization of disease-specific cardiovascular progenitors.


Accordingly, our laboratory currently integrates the study of developmental biology with tissue engineering technology and translational medicine to address the following projects:

1.  Identify the molecular determinants that control cardiac progenitor commitment, proliferation, and differentiation in mammals.

2.  Define the relationship between 2D and 3D geometric cues and cell fate determination during cardiac differentiation.

3.  Generate human models of human disease using the reporter system described above and iPS cell technology.

Collaborative Relationships:

Ibrahim Domian’s lab is a part of the Stem Cell Biology + Therapy Program.

Publications:

Click here to view Ibrahim Domian’s publications.

1. Domian, I.J., Chiravuri, M., van der Meer, P., Feinberg, A.W., Shao, Y., Shi, X., Wu, S.M., Parker, K.K., and Chien, K.R. 2009. Assembly of functional ventricular heart muscle from mouse ventricular progenitors. Science 326: 5951, 426-429.

2. Chien, K.R., Domian, I.J., and Parker, K.K. 2008. Cardiogenesis and the complex biology of regenerative cardiovascular medicine. Science 322:1494-1497.

3. Bu, L., Jiang, X., Martin-Puig, S., Caron, L., Zhu, S., Shao, Y., Roberts, D.J., Huang, P.L., Domian, I.J., and Chien, K.R. 2009. Human ISL1 heart progenitors generate diverse multipotent cardiovascular cell lineages. Nature 460:113-117.

4. Zhou B, Ma Q, Rajagopal S, Wu SM, Domian I.J., Rivera-Feliciano J, Jiang D, von Gise A, Ikeda S, Chien KR, Pu WT. (2008) Epicardial progenitors contribute to the cardiomyocyte lineage in the developing heart. Nature. 3:454(7200):109-13.

Contact Information:

Positions for postdoctoral fellows and research technicians are currently available in the Domian lab, click here. For additional information regarding current research projects and availability of job position or if you are interested in supporting our research efforts, please contact:

Ibrahim J. Domian, M.D. Ph.D.
CPZ3218 Simches Research Building
185 Cambridge St.
Boston, 02114
Phone: 617-643-6161
Fax: 617-643-3451
E-mail: idomian@partners.org


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