The Harvard Stem Cell Institute (HSCI) encompasses a diverse range of research, from investigating the basic principles of human biology to developing new therapies for patients. HSCI researchers focus both on specific disease areas—including cardiovascular diseases, kidney diseases, skin diseases, and cancer—and on processes that affect multiple disease areas, such as aging and fibrosis.
Here we highlight a few of the many exciting research advances made by HSCI scientists in 2017.
This bone marrow sample from a patient with Diamond-Blackfan anemia shows oxygen-carrying red blood cells (lighter) and white blood cells of the immune system (darker).
USING PATIENT STEM CELLS TO FIND BLOOD DISORDER DRUGS
A collaboration between George Daley, MD, PhD and Leonard Zon, MD led to the identification of a potential drug to treat Diamond-Blackfan anemia: a rare, severe blood disorder where the bone marrow does not make enough red blood cells to carry oxygen around the body.
Daley and Zon collected patient skin cells and converted them into stem cells. Then, they transformed the stem cells into a type of cell that would normally produce red blood cells. Using these cells as a model for Diamond-Blackfan anemia, they tested over a thousand chemical compounds to see if any would rescue the cells’ ability to produce red blood cells.
One compound they tested had a particularly strong effect, and successfully reversed anemia in mice.
BONE MARROW TRANSPLANTS: IMPROVING THE STEM CELL DONATION PROCESS
Because human bone marrow contains blood system stem cells, doctors use transplants of healthy bone marrow to treat patients with blood cancers or disorders. Alternatively, donors undergo drug injections over many days in order to mobilize stem cells from the bone marrow to the peripheral blood for collection.
To improve the donation process, Jonathan Hoggatt, PhD and David Scadden, MD searched for a novel drug combination that would mobilize stem cells more quickly. The combination they identified and tested in mice mobilized stem cells within 15 minutes in a single injection.
Magenta Therapeutics, a biotechnology company co-founded by Scadden, is continuing the clinical development of this new therapeutic strategy.
The inner lining of the intestine forms millions of finger-like projections. Stem cells—shown here in green—reside at the bottom and replicate daily, generating new cells to maintain the tissue.
UNDERSTANDING HOW THE INTESTINE REGENERATES
The intestine is highly regenerative by nature, as it has to withstand constant wear and tear from breaking down food, absorbing nutrients, and eliminating waste. As part of his fundamental research on the digestive tract, Ramesh Shivdasani, MD, PhD identified a previously unknown mechanism by which stem cells regenerate the inner intestinal lining.
Until now, scientists thought that when the population of stem cells in the intestinal lining is depleted, a second population of dormant stem cells becomes active.
Instead, Shivdasani showed that when stem cells were damaged in the mouse intestinal lining, a type of mature intestinal cell reverted back to a stem cell state.
GROWING SMALL INTESTINE GRAFTS FROM STEM CELLS
Severe gastrointestinal diseases can require the removal of the small intestine, which in turn leads to complications because nutrients are not absorbed into the blood. Transplants can help restore small intestine function but are currently limited by a shortage of donor organs.
To solve the problem, Harald Ott, MD took a bioengineering approach to create small intestine grafts. First, he removed the original cells from small segments of rat intestine tissue. Next, he repopulated the resulting structural scaffolds with two types of human cells: intestinal cells made from stem cells, and cells that line blood vessels.
When implanted in rats, the grafts were able to circulate blood and absorb nutrients.
Hair cells of the inner ear contain intricate hair bundles that are critical for sensing sound and transmitting it to the brain.
REPLACING HAIR CELLS IN THE EAR TO TREAT HEARING LOSS
Sounds are picked up by hair cells in the inner ear, which translate them into signals for the brain to interpret. Because these hair cells do not regenerate, any damage to them results in hearing loss.
To tackle this problem, Jeffrey Karp, PhD and Albert Edge, PhD collaborated on a method to replace hair cells in both mouse and human ear tissue. First, they identified a drug combination that increased a certain population of stem cells in the ear. Then, they converted the stem cells into hair cells.
This therapeutic approach is under further development by Frequency Therapeutics, a biotechnology company co-founded by Karp.
Doulatov, Sergei, Linda T. Vo, Elizabeth R. Macari, Lara Wahlster, Melissa A. Kinney, Alison M. Taylor, Jessica Barragan, Manav Gupta, Katherine McGrath, Hsiang-Ying Lee, Jessica M. Humphries, Alex DeVine, Anupama Narla, Blanche P. Alter, Alan H. Beggs, Suneet Agarwal, Benjamin L. Ebert, Hanna T. Gazda, Harvey F. Lodish, Colin A. Sieff, Thorsten M. Schlaeger, Leonard I. Zon, and George Q. Daley. 2017. Drug discovery for Diamond-Blackfan anemia using reprogrammed hematopoietic progenitors. Science Translational Medicine 9:eaah5645. doi:10.1126/scitranslmed.aah5645.
Hoggatt, Jonathan, Pratibha Singh, Tiffany A. Tate, Bin-Kuan Chou, Shruti R. Datari, Seiji Fukuda, Liqiong Liu, Peter V. Kharchenko, Amir Schajnovitz, Ninib Baryawno, Francois E. Mercier, Joseph Boyer, Jason Gardner, Dwight M. Morrow, David T. Scadden, and Louis M. Pelus. 2017. Rapid Mobilization Reveals a Highly Engraftable Hematopoietic Stem Cell. Cell 172:191–204.e10. doi:10.1016/j.cell.2017.11.003.
Jadhav, Unmesh, Madhurima Saxena, Nicholas K. O’Neill, Assieh Saadatpour, Guo-Cheng Yuan, Zachary Herbert, Kazutaka Murata, and Ramesh A. Shivdasani. 2017. Dynamic Reorganization of Chromatin Accessibility Signatures during Dedifferentiation of Secretory Precursors into Lgr5+ Intestinal Stem Cells. Cell Stem Cell 21:65–77.e5. doi:10.1016/j.stem.2017.05.001.
Kitano, Kentaro, Dana M. Schwartz, Haiyang Zhou, Sarah E. Gilpin, Gregory R. Wojtkiewicz, Xi Ren, Cesar A. Sommer, Amalia V. Capilla, Douglas J. Mathisen, Allan M. Goldstein, Gustavo Mostoslavsky, and Harald C. Ott. 2017.
Bioengineering of functional human induced pluripotent stem cell-derived intestinal grafts. Nature Communications 8. doi:10.1038/s41467-017-00779-y.
McLean, Will J., Xiaolei Yin, Lin Lu, Danielle R. Lenz, Dalton McLean, Robert Langer, Jeffrey M. Karp, and Albert S.B. Edge. 2017. Clonal Expansion of Lgr5-Positive Cells from Mammalian Cochlea and High-Purity Generation of Sensory Hair Cells. Cell Reports 18:1917–1929. doi:10.1016/j.celrep.2017.01.066.