Highlights

Focus on Stem Cells Update

Building the Foundation of Stem Cell Research

Stem Cell case study

Stem cell research hit its stride in the last year, which has been reflected in the research activity of Children’s Hospital Boston’s Stem Cell Program. In December, the NIH announced the approval of 13 new stem cell lines – 11 of which were developed at Children’s. Under Director Leonard Zon, MD, and Associate Director George Daley, MD, PhD, the program has expanded with a new faculty hiring and expansion of the affiliate member rolls to more than 40 researchers, and the participation in the Harvard Stem Cell Institute, which coordinates collaborative projects across Harvard-affiliated institutions.

Renewed Attention on Embryonic Stem Cells

The stem cell community has been active translating President Obama’s executive order of March 2009, “Removing Barriers to Responsible Scientific Research Involving Human Stem Cells,” into revised NIH guidelines for conducting human embryonic stem cell (hES cell) research. Several Children’s experts provided public comments on the draft proposals and the final NIH guidelines, released in July, were met with general approval and the anticipation that hES cell research will see renewed scientific attention.

Children’s Stem Cell Program is committed to making hES cells available to the research community. Children’s scientists have created 15 new hES cell lines. Under the new federal policy launched in December by President Obama, the NIH approved the first 13 hES lines to be eligible for federal funding, and 11 of the lines came from Children’s. Since the announcement, Children’s has received requests from 15 labs for over 100 cell lines. The Human Embryonic Stem Cell Core Facility at Children’s, supported by the Harvard Stem Cell Institute and directed by Thorsten Schlaeger, PhD, has provided the repository for maintaining and distributing these hES lines, as well as providing expertise and training to the stem cell community on stem cell culture.

As emphasized since the initial description of human induced pluripotent stem cells (iPS cells) reprogrammed from somatic cells, iPS cells are not identical to embryo-derived hES cells. The two cell types may show differences in their ability to differentiate into specific cells types or in their potential and suitability for therapeutic uses. This point was highlighted in a recent publication from the collaboration between Dr. Daley’s group, Dr. Schlaeger, and researchers at the Johns Hopkins University, demonstrating the difference between iPS and hES cells at the epigenetic level, i.e. the methylation status of their genomes (Nat Genet. 2009 Dec;41(12):1350-3).

Worldwide Distribution of iPS Cell Lines

Excitement continues to grow around human iPS cells, their creation, research use and therapeutic potential. Dr. Daley and In Hyun Park, PhD, have created a library of normal and disease-specific iPS cell lines (Nature. 2008 Jan 10;451(7175):141-6; Cell 2008 134(5):877-86; Blood. 2009 May 28;113(22):5476-9). In an effort to support the research community, Dr. Daley has made more than 20 iPS lines available by request to the academic research community. In the first full year since, cell lines have been distributed to over 65 laboratories worldwide. Recently, several iPS lines have been deposited into the new Massachusetts Stem Cell Bank, which was created under the “Massachusetts Life Science Strategy” as a centralized repository of new stem cell lines available to all public and private sectors of research.

Research is progressing towards understanding the process by which somatic cells can be dedifferentiated and reprogrammed into iPS cells. In November, Drs. Daley and Schlaeger's groups published a detailed study of the process of reprogramming, using live-cell staining to follow the changes in cell morphology and cell surface marker expression of the cells undergoing reprogramming. The paper provides a cautionary note, that cell colonies that appear to resemble fully dedifferentiated stem cells by morphology and by staining with typically-used markers may actually be in a partially reprogrammed state. The authors identified markers that truly pinpoint cells in the pluripotent stem cell state (Nat Biotechnol. 2009 Nov;27(11):1033-7).

Hematopoietic Stems Cells/Embryo's Heartbeat Drives Stem Cell Formation

Biologists recognized the enigma that the embryonic heart begins beating long before the tissues actually need to be infused with blood. Two groups of researchers from Boston Children's, along with collaborators, presenting multiple lines of evidence from zebrafish, mice and mouse embryonic stem cells, have shown that a beating heart and blood flow provide signals that are necessary for development of the blood cells.

One team, led by Dr. Zon, discovered that lethal mutations in zebrafish that prevent the development of a beating heart also disrupt the development of hematopoietic stem cells (HSCs). The signals that are known to regulate blood flow (such as nitric oxide, adrenergic agents and calcium channel blockers) also regulate HSC formation, independent of blood flow.

The second team, led by Dr. Daley, and Guillermo García-Cardeña, PhD, Brigham and Women's Hospital, along with scientists from Indiana University, investigated the effects of mechanical stimulation on blood formation in cultured mouse embryonic stem cells. They showed that shear stress--the frictional force of fluid flow on the surface of cells lining the embryonic aorta--increases the expression of master regulators of blood cell formation, including Runx1, and increased formation of hematopoietic progenitor cells that give rise to specific lineages of blood cells (red cells, lymphocytes, etc.).

The authors of the two papers speculate that drugs that mimic the effects of embryonic blood flow on blood precursor cells, or molecules involved in nitric oxide signaling, might be therapeutically beneficial for patients with blood diseases.

Licensed Stem Cell Treatment Moves into the Clinic

In May 2009, Children’s granted an exclusive license to Fate Therapeutics, Inc. for patent rights related to the use of compounds to stimulate stem cells. Fate was founded in 2007 with Dr. Zon as one of six founding scientists. Fate is using the fundamental biological mechanisms that guide cell fate to develop therapeutic stem cell modulators. The lead compound under the licensed rights is a stabilized prostaglandin E2 (16-, 16-dimethyl prostaglandin E2, also known as dmPGE2). Dr. Zon’s group demonstrated that dmPGE2 improves hematopoietic stem cell engraftment in transplant models. Based on this work and prior published human safety data for dmPGE2, Dr. Zon was able to obtain approval for an Investigational New Drug (IND) application from the FDA for human clinical trials and the IND was transferred to Fate concurrently with the license. Fate is currently conducting a Phase 1b trial at the Dana-Farber Cancer Institute and Massachusetts General Hospital in Boston, Massachusetts, to determine the safety and tolerability of introducing dmPGE2 during the standard course of a dual umbilical cord blood transplant in adult patients with hematologic malignancies, such as leukemia and lymphoma. Cord blood has less stringent matching criteria, so it can be available faster with lower incidence of graft versus host disease. While cord blood is commonly used for pediatric patients, it is used less frequently for adults because two cord blood units are often necessary to supply sufficient stem cells for successful engraftment. Stimulation of the cord blood stem cells may improve the transplant success, speed recovery of the immune system, provide timely treatments and reduce the risk to patients.

The Secret Lives of Stem Cells

stemcell research

Fernando Camargo, PhD, joined the Stem Cell Program this year. His research focuses on the role of stem cells in the maintenance of adult body tissues. His work on the Hippo cell signaling pathway has identified a gene that is critical for determination of organ size by expanding the populations of undifferentiated progenitor cells. The manipulation of the YAP1 gene in the liver, for example, can reversibly increase liver size by four-fold in mice. In the hematopoietic system, he has identified a gene that is key to the generation of lymphoid cells (B cells, T cells and NK cells) from multipotent progenitors. In 2009, Dr. Camargo received a NIH Director's New Innovator Award, which is a "high risk" research award given to early-stage investigators whose projects have the potential for unusually high impact.

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