HSCI Science Update: May 2011

May 18, 2011
  • How to Mend a Broken Heart

    Human cardiac muscle cells (cardiomyocytes) have a limited capacity for renewal, which is not sufficient to prevent heart failure after a heart attack. Stem cell therapy techniques can improve function after injury, but until recently scientists still wondered at the specific mechanism by which these strategies work. New research from HSCI Principal Faculty Member Richard Lee demonstrates how the technique helps the body regenerate new cardiomyoctyes. First, Lee's team induced heart attack in mice whose native cardiomyocytes were distinguishable from transplanted cells. Next, they introduced a secondary population of bone-marrow cells, called c-Kit cells, that was previously reported to improve cardiac function after injury. As expected, the treatment allowed the body to grow new cardiac muscle cells but these were neither related to the original distinguishable population nor demonstrated traits characteristic to the secondary cell population. Additionally, the researchers were able to show that a second cell population, mesenchymal stem cells, did not have the same effect.  These data indicate that the c-kit cells repair heart muscle by activating cardiomyocyte progenitor cells, rather than by transforming themselves into cardiomyoctyes or by restoring function to injured cells. Knowing the mechanism by which this cell therapy works will allow researchers to identify new, less invasive forms of treatment for cardiac patients, such as pharmacological options.

    Loffredo, F.; Steinhauser, M.; Gannon, J.; Lee, R. (2011) Bone Marrow-Derived Cell Therapy Stimulates Endogenous Cardiomyocyte Progenitors and Promotes Cardiac Repair. Cell Stem Cell 389 – 398.

  • Skin Deep: Taking Cues From Skin Cell Development to Treat Melanoma

    The neural crest is a group of embryonic stem cells that pinch off from the early spinal cord as it takes shape. Neural crest cells end up in diverse locations throughout the body, but most become melanocytes – skin cells that produce the protective pigment known as melanin. Later in life, cancerous melanoyctes are responsible for the least common but most deadly form of skin cancer – melanoma. The process of melanoma tumor initiation is analogous to the original embryonic events that lead to melanoycte differentiation. Scientists have known for several years that most of the mutations associated with melanoma occur in a gene named BRAF, but how those mutations interact with the cellular programs involved in neural crest development were less well understood. After testing multiple drugs in zebrafish, Harvard Stem Cell Institute Principal Faculty Member Leonard Zon and colleagues identified a small molecule that inhibits neural crest development in zebrafish embryos and blocks human melanoma tumor growth. Leflunamide, a common anti-arthritis drug, could be used in concert with BRAF inhibitors to strengthen melanoma therapy.

    White, R.; Cech, J,; Ratanasirintrawoot, S.; Lin, C.; Rahl, P.; Burke, C.; Langdon, E.; Tomlinson, M.; Mosher, J.; Kaufman, C.; Chen, F.; Long, H.; Kramer, M.; Datta, S.; Neuberg, D.; Granter, S.; Young, R.; Morrison, S.; Wheeler, G.; Zon, L. (2011)  DHODH modulates transcriptional elongation in the neural crest and melanoma. Nature 518 – 522.
     

  • A Better Blood Bank for Unmatched Cancer Patients

    Hematopoietic stem cells (HSCs) can differentiate into any type of mature blood cell, making them valuable in the treatment of various blood cancers, such as leukemia and lymphoma. HSC transplants are often the only curative option for these patients but such procedures require stringent matching between patient and donor cells in order to avoid rejection. For unmatched patients this means the difference between life and death. Over the last twenty years, human umbilical cord blood (hCB), which contains a variety of stem cell types including HSCs, has emerged as an option for unmatched patients. But hCB is less concentrated in HSCs than traditional bone marrow, resulting in delayed engraftment and increased transplant complications. A team of researchers led by HSCI Principal Faculty Member Trista North previously identified a method to increase hematopoietic stem cell concentration in hCB by treatment with a signaling molecule named PGE2. Recent work from the same group analyzes the long-term safety of PGE2-treated hCB transplants in non-human primates, showing no significant negative differences between experimental and control studies. The work, which provides confirmation that PGE2-treated hCB transplants are a safe option for unmatched blood cancer patients, has resulted in FDA approval for a phase I clinical trial in humans.

    Goessling, W.; Allen, R.; Guan, X.; Jin, P.; Uchida, N.; Dovey, M.; Harris, J.; Metzger, M.; Bonifacino, A.; Stroncek, D.; Stegner, J.; Armant, M.; Schlaeger, T.; Tisdale, J.; Zon, L.; Donahue, R.; North, T. (2011) Prostaglandin E2 Enhances Human Cord Blood Stem Cell Xenotransplants and Shows Long-Term Safety in Preclinical Nonhuman Primate Transplant Models. Cell Stem Cell 445 – 458.