S13-01 Master heart progenitor cells

MECHANISMS OF DEVELOPMENT

1 2 6 ( 2 0 0 9 ) S 4 0 –S 4 1

available at www.sciencedirect.com

journal homepage: www.elsevier.com/locate/modo

Symposium – Stem cells and medicine S13-02 S13-01

In vivo visualization of hematopoietic stem cell generation

Master heart progenitor cells

Elaine Dzierzak

Kenneth Chien

Erasmus University, Rotterdam, The Netherlands

Massachusetts General Hospital, Boston, United States The aorta–gonad–mesonephros (AGM) region of the vertebrate The purification, renewal and differentiation of native car-

embryo generates the first hematopoietic stem cells (HSC). The

diac progenitors would form a mechanistic underpinning for

temporal appearance of AGM HSCs is coincident with appearance

unraveling steps for cardiac cell lineage formation, and their

of hematopoietic clusters closely associated with the ventral endo-

links to forms of congenital and adult cardiac diseases. Previ-

thelium of the embryonic aorta. These clusters and ventral endo-

ously, we have reported the identification of isl1+ cardiac pro-

thelial cells express Ly-6A GFP and Runx1. As shown by

genitors in postnatal rat, mouse and human myocardium (1).

conditional deletion experiments, all adult hematopoietic cells

The discovery of native cardioblasts represents a genetically

originate from Runx1 expressing cells that have transmitted

based system to identify steps in cardiac cell lineage formation

through a VE-cadherin positive endothelial cell stage in mouse

and maturation in development and disease. A pivotal role for

midgestation [Chen etal., 2009]. Recent invitro studies performed

isl1+ progenitors in cardiovascular lineage diversification has

with mouse cells highlight a specialized endothelial cell popula-

also recently been reported by our laboratory (2), where muscle

tion, hemogenic endothelium, as the direct HSC precursor. How-

and endothelial lineage diversification arises from a single cell-

ever, HSC emergence from hemogenic endothelium has never

level decision of a multipotent isl1(+) cardiovascular progenitor

been observed invivo because of the deep location of the aorta

cell (MICP) that lies upstream of the post-natal isl1+ post-natal

within the opaque mouse embryo. Our laboratory has developed

progenitor (2). The discovery of ES cell-derived MICPs suggests

two techniques to visualize hematopoietic clusters in whole mouse

a strategy for cardiovascular tissue regeneration via their isola-

embryos: The first technique, in which the embryo is made trans-

tion, renewal and directed differentiation into specific mature

parent, allows us to quantitate hematopoietic clusters (in normal

cardiac, pacemaker, smooth muscle and endothelial cell types.

and mutant embryos) and to localize phenotypically defined HSCs.

Toward this goal, we have recently identified the Wnt/b-cate-

The second approach allows the dynamic vital imaging of aortic

nin pathway as a major component by which cardiac mesen-

HSCs as they are generated invivo. Both 3-D and time-lapse confo-

chymal cells modulate the prespecification, renewal, and

cal imaging show that HSCs (Sca1+, c-kit+, CD41+) are budding

differentiation of isl1+ cardiovascular progenitors (3). This

directly from the aortic endothelium. Within a few hours, morpho-

microenvironment can be reconstituted by a Wnt3a-secreting

logically flat endothelial cells become round and express markers

feeder layer with ES cell-derived, embryonic, and postnatal

characteristic of HSCs. HSC function is acquired in this rapid pro-

isl1+ cardiovascular progenitors. In vivo activation of b-catenin

cess. These data will be discussed, as well as the involvement of

signaling in isl1+ progenitors of the secondary heart field leads

development signalling molecules in the induction of AGM HSCs.

to their massive accumulation, inhibition of differentiation and outflow tract (OFT) morphogenic defects. In addition, the mito-

doi:10.1016/j.mod.2009.06.1025

sis rate in OFT myocytes is significantly reduced following bcatenin deletion in isl1+ precursors. Agents that manipulate Wnt signals can markedly expand isl1+ progenitors from

S13-03

human neonatal hearts, a key advance toward the cloning of

HOX transcription factor regulation of adult stem/progenitor cell

human isl1+ heart progenitors. An update on the lineage fate

behavior in response to injury

map of islet heart progenitors into differentiated progeny

Kimberly Mace

(atrial, ventricular, smooth muscle, endothelial, SA nodal, AV nodal, etc.), including the recent characterization of a novel subset of reversible, bipotent Isl1+ atrial progenitors (4), will be provided. Challenges and opportunities in moving these discoveries towards a more therapeutic application will also be highlighted. doi:10.1016/j.mod.2009.06.1024

University of Manchester, Manchester, United Kingdom The regulated recruitment and differentiation of multipotent bone marrow-derived cells (BMDCs) to sites of injury is critical for efficient tissue repair and regeneration. BMDC are a diverse population containing adult stem/progenitor cells and more mature blood and stromal cell populations. There is increasing evidence that many of these populations are more plastic than