New Blood: Tracing the Beginnings of Hematopoietic Stem Cells

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Newswise Hematopoietic stem cells (HSCs) give rise to all other blood cell types, but their development and how their fate is determined has long remained a mystery. In a paper published online this week in Nature, researchers at the University of California, San Diego School of Medicine elaborate upon a crucial signaling pathway and the role of key proteins, which may help clear the way to generate HSCs from human pluripotent precursors, similar to advances with other kinds of tissue stem cells.

Principal investigator David Traver, PhD, professor in the Department of Cellular and Molecular Medicine, and colleagues focused on the Notch signaling pathway, a system found in all animals and known to be critical to the generation of HSCs in vertebrates. Notch signaling between emitting and receiving cells is key to establishing HSC fate during development, said Traver. What has not been known is where, when and how Notch signal transduction is mediated.

Traver and colleagues discovered that the Notch signal is transduced into HSC precursor cells from signal emitting cells in the somite embryologic tissues that eventually contribute to development of major body structures, such as skeleton, muscle and connective tissues much earlier in the process than previously anticipated.

More specifically, they found that JAM proteins, best known for helping maintain tight junctions between endothelial cells to prevent vascular leakage, were key mediators of Notch signaling. When the researchers caused loss of function in JAM proteins in a zebrafish model, Notch signaling and HSCs were also lost. When they enforced Notch signaling through other means, HSC development was rescued.

To date, it has not been possible to generate HSCs de novo from human pluripotent precursors, like induced pluripotent stem cells, said Traver. This has been due in part to a lack of understanding of the complete set of factors that the embryo uses to make HSCs in vivo. It has also likely been due to not knowing in what order each required factor is needed.

Our studies demonstrate that Notch signaling is required much earlier than previously thought. In fact, it may be one of the earliest determinants of HSC fate. This finding strongly suggests that in vitro approaches to instruct HSC fate from induced pluripotent stem cells must focus on the Notch pathway at early time-points in the process. Our findings have also shown that JAM proteins serve as a sort of co-receptor for Notch signaling in that they are required to maintain close contact between signal-emitting and signal-receiving cells to permit strong activation of Notch in the precursors of HSCs.

The findings may have far-reaching implications for eventual development of hematopoietic stem cell-based therapies for diseases like leukemia and congenital blood disorders. Currently, it is not possible to create HSCs from differentiation of embryonic stem cells or induced pluripotent stem cells pluripotent cells artificially derived from non-pluripotent cells, such as skin cells that are being used in other therapeutic research efforts.

Co-authors include Isao Kobayashi, Jingjing Kobayashi-Sun, Albert D. Kim and Claire Pouget, UC San Diego Department of Cellular and Molecular Medicine; Naonobu Fujita, UC San Diego Section of Cell and Developmental Biology; and Toshio Suda, Keio University, Japan.

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New Blood: Tracing the Beginnings of Hematopoietic Stem Cells

Cellular Dynamics reports higher quarterly revenues and bigger losses

Cellular Dynamics International said revenues for the quarter that ended June 30 rose nearly 30 percent over the same quarter last year but expenses jumped even more quickly.

The Madison stem cell company reported a net loss of $8.6 million, or 54 cents a share, on $3.6 million in revenues for the most recent quarter compared with a $5.1 million net loss, or $2.92 a share, on revenues of $2.8 million for the same period last year.

Costs rose because of higher research and development expenses related to CDI's contract to set up a stem cell bank with the California Institute for Regenerative Medicine, San Francisco, and to higher expenses resulting from CDI's initial public stock offering in July 2013, the company said.

At the same time, CDI said, it has manufactured stem cells for 179 customers in the past 12 months, up from 136 customers in the previous year, and the largest customers increased their purchases by 45 percent.

"We intend to achieve profitability in the long term," said the company, which was founded in 2004 by UW-Madison stem cell pioneer James Thomson.

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Cellular Dynamics reports higher quarterly revenues and bigger losses

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WASHINGTON A U.S. researcher who co-authored controversial papers on stem cell development will quit his post at Brigham and Womens Hospital in Boston on Sept. 1, the institution said Tuesday.

Charles Vacanti, chairman of the hospitals Department of Anesthesiology, Preoperative and Pain Medicine, was involved in the publication by a Japanese institution of two theses on so-called STAP cells whose credibility came into question earlier this year.

Vacanti, known as a mentor of Haruko Obokata at the Japanese government-affiliate Riken institute who is a key author of the papers, will remain on faculty, the Boston hospital said.

Following a one-year sabbatical Vacanti intends to focus his energies on regenerative medicine and mentoring the next generation of anesthesiologists, the hospital said.

It remains unknown if his latest step is linked with the STAP cell controversy.

According to a U.S.-based expert on regenerative medicine, Vacanti of Harvard Medical School is believed to have written an email informing his colleagues and others of his intention to resign from the post.

Paul Knoepfler, associate professor at the University of Californias Davis School of Medicine, released Vacantis email on his blog on Monday.

It is with somewhat mixed emotions that I share with you my decision to step down, it reads.

Vacanti did not mention whether his decision has to do with his involvement in the papers on STAP cells that were published in the British science journal Nature in January and retracted in July after critical errors were found.

I plan to take a one-year sabbatical to contemplate my future goals, redirect my efforts and spend time doing some of the things that I enjoy most, the email says.

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How Breast Cancer Usurps the Powers of Mammary Stem Cells

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Newswise During pregnancy, certain hormones trigger specialized mammary stem cells to create milk-producing cells essential to lactation. Scientists at the University of California, San Diego School of Medicine and Moores Cancer Center have found that mammary stem cells associated with the pregnant mammary gland are related to stem cells found in breast cancer.

Writing in the August 11, 2014 issue of Developmental Cell, David A. Cheresh, PhD, Distinguished Professor of Pathology and vice-chair for research and development, Jay Desgrosellier, PhD, assistant professor of pathology and colleagues specifically identified a key molecular pathway associated with aggressive breast cancers that is also required for mammary stem cells to promote lactation development during pregnancy.

By understanding a fundamental mechanism of mammary gland development during pregnancy, we have gained a rare insight into how aggressive breast cancer might be treated, said Cheresh. This pathway can be exploited. Certain drugs are known to disrupt this pathway and may interfere with the process of breast cancer progression.

During pregnancy, a new mammary stem cell population arises, distinct from those involved in development and maintenance of the non-pregnant gland. These stem cells remodel the breasts and lactating glands in preparation for feeding the newborn child. Normally, these stem cells contribute only to early remodeling events and are switched off by the time milk production begins.

The researchers found, however, that signals regulating stem cell activation during pregnancy appear to be hijacked by cancer cells to produce faster-growing, more aggressive tumors. This normal pathway ends up contributing to the progression of cancer, said Desgrosellier, first author of the study.

A connection between pregnancy and breast cancer has long been known. But the association between pregnancy and breast cancer risk is complex. While having a child reduces a womans risk of developing breast cancer later in life, there is also an increased short-term risk for the development of a highly aggressive form of breast cancer following each pregnancy. The current study suggests that molecules important for stem cell behavior during pregnancy may contribute to these more aggressive pregnancy-associated breast cancers, a possibility the researchers plan to investigate further.

The authors are quick to point out that their findings should not be interpreted as a reason to avoid pregnancy. The signaling pathway usurped by cancer cells is not the cause of breast cancer. Rather, they said, it may worsen or accelerate a cancer caused by other factors, such as an underlying mutation or genetic predisposition.

Our work doesnt speak to the actual cause of cancer. Rather, it explains what can happen once cancer has been initiated, said Cheresh. Heres an analogy: To get cancer, you first have to start with an oncogene, a gene that carries a mutation and has the potential to initiate cancer. Think of the oncogene as turning on a cars ignition. The signaling pathway exploited by cancer cells is like applying gas. It gets the car moving, but it means nothing if the oncogene hasnt first started the process.

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How Breast Cancer Usurps the Powers of Mammary Stem Cells