Vascular smooth muscle cell (SMC) progenitors have been implicated in vascular disease, contributing to blood vessel plaque formation where they are thought to differentiate, proliferate, and secrete factors that promote atherosclerosis. Despite the importance of SMC progenitors, SMC differentiation is poorly understood. A recent study published in Circulation Research by Dr. Mansoor Husain, in collaboration with Drs. Keller and Zandstra, provides important insight into this process.

Previously, Dr. Husain's team found that the c-Myb transcription factor is critical for SMC differentiation. In the current study, McEwen Centre researchers discovered that c-Myb levels are tightly regulated during the earliest stages of differentiation of embryonic stem cells (ESCs) into cardiovascular progenitors, which subsequently give rise to a variety of cardiovascular cell types, including SMCs. In order to identify which cell populations were capable of becoming SMCs, both wild-type and c-myb knockout ESCs were sorted using two markers that are expressed on cardiovascular progenitors: platelet-derived growth factor receptor α (PDGFRα) and the vascular endothelial growth factor receptor 2 (VEGFR2). Strikingly, it was found that in the absence of c-Myb, cells positive for VEGFR2 and negative for PDGFRα (V+/P-) do not appear when they should (day 3.5 of differentiation). Further experiments found that V+/P- cells were the only population, when treated with retinoic acid, capable of fully differentiating into mature SMCs. Chromatin immunoprecipitation and promoter-reporter assays showed that c-Myb binds to the VEGFR2 promoter and activates transcription, and that this binding is temporally regulated during the differentiation process.

By identifying the population of early cardiovascular progenitors that give rise to SMCs, as well as defining the mechanism by which the c-Myb transcription factor is involved, Dr. Husain's team has provided valuable insight into SMC differentiation—results that may be exploited to unlock the regenerative potential of ESCs, while furthering our understanding of vascular disease.

Regulated expression and role of c-Myb in the cardiovascular-directed differentiation of mouse embryonic stem cells. Ishida M, El-Mounayri O, Kattman S, Zandstra P, Sakamoto H, Ogawa M, Keller G, Husain M. Circ Res. 2011 Nov 23. [Abstract]

In Tribute to the Pioneers of Stem Cell Research

Drs. Ernest McCulloch and James Till, credited for devising the first functional definition of a stem cell, were honoured in a ceremony held at UHN on February 1, 2011—the 50th anniversary of the publication of their findings. As part of the event, a memorial was held for Dr. McCulloch, who passed away earlier this year. Friends and colleagues spoke of his legacy as an unfailing mentor to the next generation of stem cell scientists.

Welcome to Stem Cell City

With the Premier of Ontario Dalton McGuinty on hand, the McEwen Centre launched Stem Cell City on June 15, 2011. This project was created to promote awareness and support for the use of regenerative medicine to defeat the major diseases of our time. Show your support: Click here to become a citizen of Stem Cell City.

Toronto Welcomes Over 3600 Stem Cell Researchers

The 9th Annual International Society for Stem Cell Research, co-sponsored by the McEwen Centre, was held this year in Toronto. Highlights from the meeting included a keynote lecture by Robert S. Langer and an "Ernest McCulloch Memorial Lecture" presented by Dr. John Dick. As well, the inaugural McEwen Centre Award for Innovation was presented to Drs. Kazutoshi Takahashi and Shinya Yamanaka for their groundbreaking work on the discovery of iPS cells at the Center for iPS Cell Research and Application, Kyoto University, Japan.

CCRM Ushers in the Future of Medicine

The Centre for Commercialization of Regenerative Medicine was launched in June 2011. Led by Dr. Peter Zandstra, the Centre aims to "create and sustain a global nexus for Regenerative Medicine commercialization" by bringing together world-renowned stem cell scientists with strong business leadership.

Congratulations to the following McEwen researchers who received distinguished awards in 2011:

Dr. Ren-Ke Li was made a Fellow of the Canadian Academy of Health Sciences.

Dr. Freda Miller and Dr. Molly Shoichet were elected as Fellows of the American Association for the Advancement of Science.

Dr. Molly Shoichet was named to the Order of Ontario—the Province's highest honour.

Dr. Shaf Keshavjee published his findings in the New England Journal of Medicine from a clinical trial on the effectiveness of the Toronto XVIVO Lung Perfusion System. The study showed that this system can be used to effectively treat, reassess, and improve the function of high-risk donor lungs prior to transplantation.

Dr. Andras Nagy and Dr. Timo Otonkoski found that induced pluripotent stem cells (iPSCs) contain higher frequencies of genetic abnormalities. These results, which were featured in Nature, highlight the importance of monitoring the genetic integrity of iPSCs.

Earlier this year, the lab of Dr. John Dick provided new insights into leukemia. The team found that multiple genetically distinct leukemia-initiating cell subclones exist in single leukemia samples, suggesting that effective cancer treatments must target all subclones within tumours (Nature). Furthermore, by isolating leukemia stem cells, they were able to identify a stem cell gene signature, published in Nature Medicine, capable of predicting disease outcome for acute myelogenous leukemia. Also with a focus on blood research, Dr. Dick's laboratory identified integrin CD49f as a reliable marker for the isolation of hematopoietic stem cells at quantities sufficient for use in clinical applications (Science).

In a Cell Stem Cell article, the lab of Dr. Gordon Keller showed that, by monitoring and optimizing a number of signaling pathways, cultures highly enriched in cardiomyocytes can be generated without the need for cell sorting. Furthering these findings, a second manuscript (Nature Biotechnology), identified a cell-surface marker that can be used to isolate human cardiomyocytes to near purity—findings with important implications for heart disease models and therapeutics.

Work published in Nature Materials from the lab of Dr. Molly Shoichet describes a new technique for the creation of complex, three-dimensional gradients of effector molecules. The technique will allow for the detailed study of cell niches.

Dr. Derek van der Kooy’s laboratory advanced their studies of pancreas-derived multipotent precursors. They found that these cells can generate insulin-producing beta cells that, when transplanted, improve glucose and body weight regulation in a mouse model of diabetes (Cell Stem Cell).

The McEwen Centre wishes everyone Happy Holidays
and all the best for 2012!