Learning from Disease
While we often look to stem cell research models to help us better understand disease, new work by HSCI Principal Faculty member Bjorn Olsen, PhD, and colleagues takes the opposite approach. Their recent research explores a mechanism at play in the rare disease known as fibrodysplasia ossificans progressiva (FOP) that transforms endothelial cells into stem-like cells. FOP is characterized by bone formation in areas outside of the skeleton. The researchers found a surprising source for these pathological bone and cartilage cells. Instead of originating as osteoblasts (bone stem cells) or chondrocytes (cartilage stem cells), the diseased cells are endothelial in nature, such as those from the inner lining of blood vessels. FOP patients carry a mutation in the gene that encodes the protein ALK2. Olsen's team found that when this protein is constitutively active, a cellular transition takes place in which blood vessel cells are reprogrammed to have the potential to develop into a number of other cell types - including cartilage and bone cells. The implications of this research are twofold: not only do we gain a keener understanding of the debilitating FOP pathology and potential therapeutic approaches, but we also walk away with additional clues about the genetic mechanisms regulating multipotency.
Medici, D., Shore, E., Vitali, L., Kaplan, F., Kalluri, R., Olson, B. (2010) Conversion of vascular endothelial cells into multipotent stem-like cells. Nature Medicine 16, 1400-6. Epub 2010 November 21.
Gutsy Guy: HSCI Scientist Helps Uncover a "Master Regulator" Protein in the Intestine
As Ramesh Shivdasani, MD/PhD, says on his website, "the gastrointestinal tract is an amazing organ." The GI lining replenishes itself every three days, and this constant proliferation makes the gut an excellent model to investigate gene regulation during cellular differentiation. Shivdasani and his colleagues recently used an epigenomic approach to demonstrate that the transcriptional factor CDX2 is widely active in regulating gene expression in both dividing and mature intestinal cells. Epigenomic studies look at the role that extra-genetic factors play in cellular processes. Here, CDX2 appears to have an even more important regulatory effect on cell differentiation than even the DNA sequences it interacts with. The researchers demonstrate that CDX2 is necessary for the normal development of an embryonic gut as well as the continued, successful functioning of adult intestines. Its presence in the cellular environment is crucial to an organism's survival. But CDX2 doesn't work alone. Shivdasani and his team found that two other important transcription factors, GATA6 and HNF4A, help CDX2 in its regulation of cellular differentiation in progenitor and differentiated cells, respectively. Together with these condition-specific co-regulators, CDX2 plays a critical role in intestinal cell proliferation acting as a "master regulator." This research validates CDX2 as a potential therapeutic target. More generally, the work upholds the use of the gut as a model system for learning about the regulation of cellular differentiation, and elucidates the role of additional players in the development, differentiation, and proliferation processes.
Verzi, M., Shin, H., He, H., Sulahian, R., Meyer, C., Montgomery, R., Fleet, J., Bown, M., Liu, X., Shivdasani, R. (2010) Differentiation-Specific Histone Modifications Reveal Dynamic Chromatin Interactions and Partners for the Intestinal Transcription Factor CDX2. Developmental Cell 19, 713-26.
Blood: A Balancing Act Orchestrated by Lkb1
Coming from its Greek roots, the word hematopoiesis means "to make blood." The process is repeated millions of times a day in every individual mammal and begins with hematopoietic stem cells, or HSCs, which have the ability to mature into any of the various blood cell types. This constant replenishment requires HSCs to fluctuate between dormant and proliferative states whenever necessary. While this energetic balancing act is still poorly understood, recent work by HSCI Affiliate Faculty member Nabeel Bardeesy, PhD, gives us a new piece of the puzzle. The tumor suppressor protein Lkb1 is known for its role in cellular metabolism and growth and is readily detectable in HSCs, making it a prime suspect in Bardeesy's quest to better understand hematopoiesis. The research team found that indeed, this single molecule plays an enormous role in regulating the dynamic hematopoietic system. First, the team genetically engineered Lkb1-deficient mice, which had a staggeringly low survival rate of 7%, their blood literally degrading within 30 days. Next, they transplanted healthy mice with mutated Lkb1-deficient HSCs and found similar results - death within 12 weeks and bone marrow degradation in just five days. They went on to show that Lkb1 is intrinsically necessary to maintain the subtle dance between HSC quiescence and proliferation and that this regulation is largely independent of the other proteins commonly linked to Lkb1 function. The next step of research will be to understand how the HSC population responds to its metabolic environment and how Lkb1 is implicated in that response.
Gurumurthy, S., Xie, S., Alagesan, B., Kim, J., Yusuf, R., Saez, B., Tzatsos, A., Ozsolak, F., Milos, P., Ferrari, F., Park, P., Shirihai, O., Scadden, D., Bardeesy, N. (2010) The Lkb1 metabolic sensor maintains haematopoietic stem cell survival. Nature, 468, 659-664.