The Cardiovascular Research Center at Massachusetts General Hospital

Caroline Burns

Science

One long-term goal of the laboratory is to identify and understand the genetic pathways regulating cardiac progenitor cell fate during embryogenesis. Cardiovascular disease is the leading cause of mortality in adults and is the principle non-infectious cause of death in children. While many treatment regimens exist, none provide a long-term cure as functional restoration of the diseased heart is compromised by the inability of postnatal cardiac muscle cells to proliferate. A number of clinical trials using bone marrow or cord blood stem cells have attempted to regenerate heart muscle after acute myocardial infarction, however, there is little or no evidence of muscle regeneration leading to largely disappointing clinical outcomes. Thus, there is a critical need to identify and activate the most primitive cardiovascular stem cells (CSCs) with the primary goal of generating replacement tissue for damaged heart muscle, valves, and vessels.

Endogenous CSC pools have been recently described that may act to normally replace apoptotic cardiomyocytes at extremely low, basal levels during adulthood. Although these CSCs can self-renew and proliferate, they are extremely rare, thus limiting their potential to contribute substantially to diseased heart tissue. Thus, my laboratory is interested in identifying the normal mechanisms by which these CSCs are specified, expanded, and differentiated during embryonic development to ultimately augment the activity of either endogenous or transplanted adult CSCs for clinical use.

The zebrafish is an excellent model system to study fate determination and stem cell biology as there are distinct genetic and transplantation advantages. As the developmental genetics of organ formation are highly conserved between fish and mammals, the pathways affecting fate decisions in zebrafish can be directly compared to that of humans. We are identifying master CSC pools within the developing teleost and dissecting their initial induction using both genetic and chemical-based screening strategies. Moreover, we are prospectively isolating these populations based on fluorescent marker gene expression and transplanting them into whole blastulae to uncover their developmental potential in vivo. Using different mutant lines, we can also reveal the effect specific mutations bear on their differentiation abilities. Moreover, through the creation of inducible heart disease models, we will transplant these embryonic populations into adult animals to investigate their regenerative capacity.

Zebrafish Publications

Peng, C.-Y., H. Yajima, C. E. Burns, L. I. Zon, S. S. Sisodia, S. L. Pfaff, and K. Sharma. (2007). Notch and MAML regulate Scl-dependent Interneuron Cell Fate. Neuron 53: 813-827.
Burns, C. E., Traver, D., Mayhall, E., Shepard, J. L., and Zon, L. I. (2005). Hematopoietic stem cell fate is established by the Notch-Runx pathway. Genes Dev 19: 2331-2342.
Ransom, D.G., N. Bahary, K. Niss, D. Traver, C. Burns, N.S. Trede, N. Paffett-Lugassy, W.J. Saganic, C.A. Lim, C. Hersey, Y. Zhou, B.A. Barut, S. Lin, P.D. Kingsley, J. Palis, S.H. Orkin, and L.I. Zon. (2004). The Zebrafish moonshine Gene Encodes Transcriptional Intermediary Factor 1gamma, an Essential Regulator of Hematopoiesis. PLoS Biol 2: E237.
Burns, C. E., T. DeBlasio, Y. Zhou, J. Zhang, L. Zon, and S.D. Nimer. (2002). Isolation and characterization of runxa and runxb, zebrafish members of the runt family of transcriptional regulators. Exp Hematol 30: 1381-9.
Erter, C., T. Wilm, N. Basler, C.V.E. Wright, and L. Solnica-Krezel. (2001). Ventrolateral Wnt8 Function is Required for Neural Posteriorization in vivo. Development. 128, 3571-3583.
Gonzalez, E., K. Fekany-Lee, A. Carmany-Rampey, C. Erter, J. Topczewski, C.V.E. Wright, and L. Solnica-Krezel. (2001). Head and trunk in zebrafish arise via coinhibition of BMP signaling by bozozok and chordino. Genes Dev 14: 3087-3092.
Erter, C., L. Solnica-Krezel, and C.V.E. Wright. (1998). Zebrafish nodal-related 2 Encodes an Early Mesendodermal Inducer Signaling from the Extraembryonic Yolk Syncytial Layer. Dev. Biol. 204, 361-372.