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Defining the map back to stemness

Posted By Connections Editor, Friday, May 1, 2015
Updated: Wednesday, April 29, 2015

By: Eirini Trompouki and Teresa V. Bowman 

 

Thousands of bone marrow transplantations take place each year in US alone.
Although broadly employed, the use of transplantation is hampered by the lack of appropriate donor cells. Even when there is a matched donor, the number of cells is often insufficient, thus hampering the full utility of the therapy. There is clearly an immediate need to enhance our ability to create or expand hematopoietic stem cells (HSCs). To this end, George Daley and Derrick Rossi, both from Harvard Medical School, presented their approaches, for overcoming this challenge at the most recent ISEH webinar entitled “Hematopoietic specification from pluripotent cell lines vs. reprogramming of somatic cells” (now available for viewing online at http://www.iseh.org/?ISEHWebinars).

Reprogramming of differentiated cells to progenitor cell types holds great promise for medical applications. However, reprogramming to HSCs has proven particularly challenging. The Daley and Rossi groups as well as others including the webinar moderator, Kateri Moore and her group from Mt. Sinai Hospital, have devised approaches to reprogram various cell types back to a multipotent state. Dr. Daley’s group is striving to impart long-term multilineage potential to embryonically derived human hematopoietic progenitors. His lab has established a protocol to direct human embryonic stem cells or induced pluripotent stem cells to a primitive myeloid progenitor. Using this population as starting material and following a Yamanaka-like strategy to reprogramming, Daley’s group determined that five factors (HOXA9, RORA, ERG, SOX4, and MYB) were sufficient to promote multipotent engraftment potential (Doulatov et al. Cell Stem Cell 2013). They have now expanded the transcription factor repertoire to include NFIA and DACH2, which are needed to convey better lymphoid potential, a population that is usually under-represented in most blood-forming efforts. Finally, Dr. Daley also showed that these methods can be successfully used to model human disease. He presented an unpublished model of a hereditary blood disorder, Diamond-Blackfan Anemia, demonstrating that many facets of the disease can be recapitulated both in vitro and in vivo. He ended with a short vignette on a chemical screen that uncovered autophagy as a novel therapeutic target for suppressing the erythroid defects in DBA.

Dr. Rossi discussed his lab’s approach to reprogram mature progenitor and effector blood cells back to multilineage long-term HSCs using a murine model. After intense screening, the Rossi group defined a set of six factors (Hlf, Pbx1, Prdm5, Runx1t1/Eto, Lmo2, and Zfp37) that are needed to reprogram either common myeloid progenitors of pre/pro-B cells into induced hematopoietic stem cells (iHSC) (Riddell et al. 2014). After further technical refinement, they also demonstrated that inclusion of Meis1 and Mycn and importantly the use of polycistronic vectors enhanced reprogramming. Thus, specific factors but also their respective expression levels can severely affect reprogramming. Having successfully employed the powers of an in vivo system, Dr. Rossi also eluded to on-going work in his laboratory to improve ex vivo culture conditions for HSC expansion using small molecule screening. The hope is to establish reprogramming conditions that can then be used to generate iHSCs ex vivo.

During the webinar it became clear that there is a lack of commonality among the transcription factors identified by the Daley and Rossi groups as well as others such as Kateri Moore or Shahin Rafii (Weill Cornell). Do factors identified in murine systems play a conserved role in humans? How important is the initial cell that is used for reprogramming? The investigators agree that the starting cell type and epigenetic state influence or even determine the identity of factors needed to reprogram a given cell type. From the discussion, it was well understood that it is much easier to reprogram closely related blood cells than other differentiated cell types like fibroblasts. The multiple players in the HSC reprogramming field now have a wide choice of potential factors to try to reprogram their favorite cell type. The investigators agreed the more the merrier when it comes to labs contributing to the field of HSC reprogramming. Working together to solve the problem will only improve the system and advance science faster. Throughout the webinar, it was gratifying to hear not only interesting data but also the collaborative nature of the work and the openness of the investigators to share their reagents. With this pace and attitude, there is a high possibility that deriving patient-specific HSCs is not science fiction but a proximal reality.

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