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Cai Lab - Research

Overview

    Cardiogenesis, the induction and subsequent development of the heart, is a critical event during embryogenesis. Mutations in genes expressed in the early heart cause defective cardiac development, and are responsible for embryonic lethality and congenital heart disease, occurring in ~1% of live births and 10% of stillbirths in humans. The Cai laboratory uses mouse as a model system to study the molecular pathways controlling heart development and disease. Uncovering signaling cascades underlying early heart development also has great implications for the research of cardiac regenerative biology.

    Dr. Cai’s previous research has showed that Isl1 (Islet1), a Lim-homeodomain transcription factor, labels a cardiac progenitor population that gives rise to the majority of cardiac segments (right ventricle, outflow tract and atria).  Loss of Isl1 results in a malformed heart that lacks these cardiac segments during early heart development (Fig. 1). In addition to the study of Isl1, Dr. Cai also discovered that T-box transcription factor Tbx20 plays critical roles in regulating cardiac cell proliferation and specification (Fig. 2). More recently, Dr. Cai identified another cardiac progenitor population, Tbx18-expressing proepicardial and epicardial cells that can gives rise to both myocytes and non-myocytes cardiac lineages during early heart development (Fig. 3). The Cai laboratory is currently performing research to decipher the transcriptional networks of Isl1 and Tbx20 in heart development. They are also interested in exploring the therapeutic potential of Isl1 and Tbx18 progenitor cells in cardiac repair and regeneration.



Figure 1.  Lim-homeodomain transcription factor Isl1 is not expressed in the differentiated cardiac cells (A-D). Isl1 (notched arrows in A-D) is not co-expressed with MLC2a (unnotched arrows in A-D) in the cardiac crescent (A) and heart tube (B-D). Lineage tracing with Isl1:IRES-Cre/R26Rlacz mice revealed Isl1 progenies can give rise to cardiac cells in the outflow tract (OT),  right ventricle (RV), and some cells in the atria and left ventricle (E,F). Scanning electron microscopy (SEM) revealed Isl1 homozygous null (Isl1-/-) hearts do not loop, and are missing outflow tract (OT), and right ventricle (RV) (G,H).

I. A working model demonstrates how Isl1 cardiac progenitors contribute to heart formation. Isl1 is expressed in the foregut endoderm and splanchnic mesoderm (green). Isl1 cells can migrate and differentiate into cardiomyocytes (blue) as heart develops (E7.5-9.5). It is important to note that Isl1 expression gradually turns off as migration and differentiation occurs. For details, please see Developmental Cell, 2003, 5(6):877-89.



Figure 2.  T-Box transcription factor Tbx20 is highly expressed in heart during early embryogenesis in mouse (A,B). Hearts of Tbx20 homozygous null mice (Tbx20-/-) are severely hypoplastic relative to control littermates (C,D). T-Box transcription factor Tbx2 is ectopically expressed in Tbx20-/- hearts (E,F), whereas expression of N-myc (I,J) and phosphorylated histone H3 (G,H) is downregulated, demonstrating a decreased proliferation in Tbx20-/- cardiac cells relative to control littermates.


K. A working model for regional control of proliferation and expression of chamber specific genes by Tbx20 and Tbx2. In chamber myocardium, Tbx20 represses Tbx2, preventing its repression of N-myc and chamber-specific genes (Nppa, Cited1, Cx40, Chisel, etc.). Tbx20 can also directly bind and activate N-myc, allowing for higher rates of proliferation in the cardiac chamber. Tbx2 in non-chamber myocardium represses chamber specific genes and N-myc, resulting in lower rates of proliferation. For details, please see Development, 2005, 132(10):2475-87.



Figure 3.  T-Box transcription factor Tbx18 is specifically expressed in the proepicardium (unnotched arrows in A,B) and epicardium (notched arrows in A,C,D) during mouse embryogenesis. Lineage tracing with Tbx18:Cre/R26Rlacz mice revealed Tbx18  descendants give rise to cardiomyocytes in the ventricular septum (E,F, demonstrated by co-staining of Troponin T (red, cardiomyocyte marker) and β-galactosidase (green)). Tbx18-expressing cells also give rise to coronary smooth muscle cells (G, arrows) and cardiac fibroblasts (H, arrows).


I. A working model for the contribution of Tbx18 lineages to myocyte and non-myocyte populations within the heart. At E9.5, Tbx18 proepicardial cells begin to migrate onto the heart to form the epicardium. At E10.5, Tbx18 epicardial cells begin to migrate into the forming ventricular septum and adopt a myocardial cell fate.  At E12.5, vascular support cells derived from Tbx18 lineages are first observed within the heart. By neonatal stage, Tbx18 lineages are observed to comprise a substantial proportion of myocytes within the ventricular septum, and scattered myocytes within each of the cardiac chambers (blue). Tbx18 lineages contribute substantially to vascular support cells (yellow), and to approximately one third of cardiac fibroblasts. LA/RA, left/right atrium; LV/ RV, left/right ventricle; VS, ventricular septum; SV, sinus venosus; and FG, foregut. For details, please see Nature, 2008, 3;454(7200):104-8.

 
lab info



Chen-Leng Cai
ASSOCIATE PROFESSOR
chenleng.cai@mssm.edu

212-824-8917 (office / lab)
212-241-3310 (fax)

lab members:
Cai, Xiaoqiang
Sultana, Nishat
Zhang, Lu

see photos and more here.
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key publications

2013
Cai X, Zhang W, Hu J, Zhang L, Sultana N, Wu B, Cai W, Zhou B, Cai CL,
Tbx20 acts upstream of Wnt signaling to regulate endocardial cushion formation and valve remodeling during mouse cardiogenesis.
Development., 140(15): 3176-87.

Grisanti L, Clavel C, Cai X, Rezza A, Tsai SY, Sennett R, Mumau M, Cai CL*, Rendl M*.,
Tbx18 targets dermal condensates for labeling, isolation, and gene ablation during embryonic hair follicle formation.
J Invest Dermatol., 133(2): 344-53. (*co-corresponding authors)

2011
Cai X, Nomura-Kitabayashi A, Cai W, Yan J, Christoffels VM, Cai CL.,
Myocardial Tbx20 regulates early atrioventricular canal formation and endocardial epithelial-mesenchymal transition via Bmp2.
Dev Biol., 360(2): 381-90.

2008
Cai CL, Martin JC, Sun Y, Cui L, Wang L, Ouyang K, Yang L, Bu L, Liang X, Zhang X, Stallcup WB, Denton CP, McCulloch A, Chen J, Evans SM.,
A myocardial lineage derives from Tbx18 epicardial cells.
Nature, 454(7200), 104-8.

2006
Cai CL, Zhou W, Yang L, Bu L, Qyang Y, Zhang X, Li X, Rosenfeld MG, Chen J, Evans S.,
T-box genes coordinate regional rates of proliferation and regional specification during cardiogenesis. 
Development, 132(10), 2475-87.

2003
Cai CL, Liang X, Shi Y, Chu PH, Pfaff SL, Chen J, Evans S.,
Isl1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart.
Dev Cell, 5(6), 877-89.

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