Profile

Mark W. Majesky, PhD

Mark W. Majesky, PhD

Children's Title: Director of Myocardial Regeneration Initiative; Principal Investigator

Academic Title: Professor of Pediatrics

Research Center: Center for Developmental Biology and Regenerative Medicine

"I love studying developmental biology and all its implications. It has enriched my life in many ways beyond my job. Theres so much beauty in the field for me, and I get so excited when I learn about these biological mechanismsI would study them even if they werent part of my career. Knowing that it can have a tangible impact on children makes it worthwhile."

Mark began his research training at the University of Washington (UW) and now returns to the Pacific Northwest to join the Center for Developmental Biology and Regenerative Medicine to lead its groundbreaking program in stem cell biology and regenerative medicine as the director of the Myocardial Regeneration Initiative.

Making A Difference

Overview

Research Description

Professional History

Graduate School:
University of Washington, Department of Pharmacology

Postdoctoral:
University of Washington, Vascular Biology

Faculty:
Assistant Professor, Baylor College of Medicine, Houston, TX
Associate Professor, Baylor College of Medicine, Houston, TX
Professor, University of North Carolina, Chapel Hill, NC


Molecular Basis of Coronary Vessel Development:

We study the development and differentiation of coronary blood vessels. Coronary progenitors are found in the proepicardium, a transient cell population that arises independently of the heart itself. In evolution, the appearance of the proepicardium correlates with the transition of the heart from a primitive tubular structure with a thin-walled, epithelial-type myocardium, as is found in pre- and early chordates, to a thick multilayered pumping organ found in most vertebrates.

Fate mapping studies show that proepicardial cells are the forerunners for the endothelium, smooth muscle and adventitial cells of the coronary vasculature. Formation of coronary vessels occurs by an epithelial to mesenchymal transformation (EMT) of proepicardial cells at the surface of the heart, followed by vasculogenesis in the subepicardial layer, assembly and remodeling of a primitive coronary plexus, and investment by coronary smooth muscle cells (CoSMCs).

We apply molecular biological and developmental genetic approaches to identify pathways for CoSMC commitment and differentiation during heart development. We use both chick and mouse models to explore mechanisms that couple proepicardial cell EMT and transcriptional activation of CoSMC target genes. Current projects in the lab employ transgenic and knockout mice to examine the role of sonic hedgehog signaling, rhoGTPase activation, and cytoskeletal remodeling in the stimulation of SRF and Tbxdependent transcription that mediates proepicardial cell differentiation to CoSMCs.


Role of Tbx18 in Murine Development:

T-box-containing proteins play critical roles as transcription factors that regulate cell fate and differentiation in development. Tbx18 is highly expressed in septum transversum and proepicardium. We used gene targeting in ES cells to produce Tbx18 knockout mice, which die shortly after birth with skeletal, renal and cardiac defects. Current projects aim to characterize these defects in detail, identify binding partners and gene targets for Tbx18, and prepare a conditional null allele for analysis of Tbx18 function in adult mice. Tbx18 is highly expressed in mesothelial membranes that line the pleural, pericardial and peritoneal cavities. These membranes are prone to fibrotic reactions to injury. Fibrosis limits regeneration and repair, restricts end organ function, and is an important cause failure in renal dialysis, and reproductive function after pelvic surgery. Adult models of mesothelial wound repair will allow us to genetically dissect key steps leading to pathological fibrosis.

Another goal of this project is to identify enhancer elements that direct Tbx18 expression to the proepicardium. Using rVISTA phylogenetic sequence comparisons, several conserved intronic elements have been identified as candidate proepicardial enhancers. These elements have been multimerized, ligated into minimal promoter vectors, and are being tested in transgenic frogs and mice.


Sonic Hedgehog Signaling and Adventitial Stem Cells

Blood vessels are continuously undergoing formation, regression, remodeling and repair throughout life. We found a domain of sonic hedgehog signaling restricted to the adventitial layer of artery walls which supports a population of resident vascular stem and progenitor cells. When removed from the adventitial niche environment, these resident progenitors differentiate to mural-like cells (pericytes and smooth muscle cells) in vitro, and closely associate with nascent microvessels in angiogenesis assays in vivo. Maintenance of an adventitial stem/progenitor cell phenotype is dependent upon expression of KLF4. The role of sonic hedgehog signaling in development of the adventitia is an active area of current investigation in the laboratory.

Lab URL

http://www.seattlechildrens.org/research/developmental-biology-regenerative-medicine/majesky-lab/

Research Focus Area

Genetics, Stem Cell Biology, Developmental Biology

Publications

  • Hoglund VJ, Dong XR, Majesky MW
    Neointima formation: a local affair.
    Arteriosclerosis, thrombosis, and vascular biology , 2010 Oct. : 1877-9
  • Yoshida T, Gan Q, Franke AS, Ho R, Zhang J, Chen YE, Hayashi M, Majesky MW, Somlyo AV, Owens GK
    Smooth and cardiac muscle-selective knock-out of Kruppel-like factor 4 causes postnatal death and growth retardation.
    The Journal of biological chemistry , 2010 July 2 : 21175-84
  • Majesky MW
    Developmental biology in the vasculature--review series.
    Arteriosclerosis, thrombosis, and vascular biology , 2009 May : 622
  • Regan JN, Majesky MW
    Building a vessel wall with notch signaling.
    Circulation research , 2009 Feb. 27 : 419-21
  • Passman JN, Dong XR, Wu SP, Maguire CT, Hogan KA, Bautch VL, Majesky MW
    A sonic hedgehog signaling domain in the arterial adventitia supports resident Sca1+ smooth muscle progenitor cells.
    Proceedings of the National Academy of Sciences of the United States of America , 2008 July 8 : 9349-54
  • Dong XR, Maguire CT, Wu SP, Majesky MW
    Chapter 9. Development of coronary vessels.
    Methods in enzymology , 2008 : 209-28
  • Majesky MW
    Developmental basis of vascular smooth muscle diversity.
    Arteriosclerosis, thrombosis, and vascular biology , 2007 June : 1248-58
  • Majesky MW
    Organizing motility: LIM domains, LPP, and smooth muscle migration.
    Circulation research , 2006 Feb. 17 : 306-8
  • Hirschi KK, Majesky MW
    Smooth muscle stem cells.
    The anatomical record. Part A, Discoveries in molecular, cellular, and evolutionary biology , 2004 Jan. : 22-33
  • Majesky MW
    Development of coronary vessels.
    Current topics in developmental biology , 2004 : 225-59
  • Majesky MW
    Decisions, decisions...SRF coactivators and smooth muscle myogenesis.
    Circulation research , 2003 May 2 : 824-6
  • Majesky MW
    Vascular smooth muscle diversity: insights from developmental biology.
    Current atherosclerosis reports , 2003 May : 208-13
  • Majka SM, Jackson KA, Kienstra KA, Majesky MW, Goodell MA, Hirschi KK
    Distinct progenitor populations in skeletal muscle are bone marrow derived and exhibit different cell fates during vascular regeneration.
    The Journal of clinical investigation , 2003 Jan. : 71-9
  • Chang DF, Belaguli NS, Iyer D, Roberts WB, Wu SP, Dong XR, Marx JG, Moore MS, Beckerle MC, Majesky MW, Schwartz RJ
    Cysteine-rich LIM-only proteins CRP1 and CRP2 are potent smooth muscle differentiation cofactors.
    Developmental cell , 2003 Jan. : 107-18
  • Majesky MW
    Mouse model for atherosclerotic plaque rupture.
    Circulation , 2002 Apr, 30 : 2010-1
  • Majesky MW
    Smooth muscle-specific transcription without a CArG box element.
    Circulation research , 2002 Apr, 5 : 628-30