Hematopoietic stem cells (HSCs) have the extraordinary capacity to differentiate into all the cell types in the hematopoietic system while maintaining their own population through self-renewal. Disturbance in this balance between self-renewal and differentiation can lead to fatal hematologic malignancies, diseases that can be effectively treated with healthy HSCs for restoration of normal hematopoiesis and immunity. It is critical that we understand the mechanisms governing stem cell function in order to design more effective strategies to prevent their dysfunction and harness their therapeutic potential. Currently, our knowledge of marrow stem cells is based almost solely on very small subpopulations of highly purified, predominantly quiescent HSCs. However, we have shown that a significant population of cycling HSCs is lost during this purification process, and that this cycling stem cell pool can be, in part, recovered within the Lineage positive cellular fraction. Therefore, we propose that the highly purified HSCs, while exhibiting potent stem cell activity, are not fully representative of the total stem cell potential within marrow. In these studies, we propose to fully characterize a population of stem cells in marrow that are discarded with conventional HSC isolation strategies. We will determine their phenotype, cell cycle status, molecular signature and explore the mechanisms responsible for their loss during standard HSC purification strategies. We anticipate that the results of these experiments will have significant implications for the future study of HSCs. First, we are hopeful that characterization of this population of understudied stem cells within marrow will lead to a valuable expanded population of HSCs for clinical use. Second, virtually all our knowledge about HSCs--their cell cycle state, their bone marrow niche, and the transcriptional pathways governing their self-renewal and differentiation behavior--come from studies on only the highly purified HSCs. Thus, we expect that such fundamental characteristics of stem cell function will need to be re-explored within the context of the broader population of stem cells in marrow in order to gain a more comprehensive and accurate view of hematopoietic stem cell biology. My long-term career goal is to become an independent scientific investigator and leader in the field of hematopoietic stem cell biology. During my Hematology/Oncology fellowship at Brown University, and now as an Assistant Professor in the Division of Hematology/Oncology at Rhode Island Hospital, my clinical experience coupled with my research experience in Dr. Peter Quesenberry's stem cell laboratory have provided me with a strong foundation in the field of stem cell biology. This stem cell experience greatly complements my earlier graduate training in the Medical Scientist Training Program at the University of Pittsburgh, during which time I gained invaluable research experience in molecular and cellular biology. However, as a relatively new investigator in the field, I have important educational gaps that would be filled by the additional training facilitate by this career development award. Specifically, the opportunities afforded by this Mentored Career Development Award will greatly strengthen my academic, technical, statistical, and grant- writing skills, thereby greatly increasing the likelihood that I will be a successful, highl-competitive R01-funded researcher in the future.

Public Health Relevance

Hematopoietic stem cells are special cells in the body that are responsible for generating all the blood cells in the circulatory system. Many cancers of the blood are caused by abnormalities in these stem cells. In addition, the ability of these cells to produce all the blood cells in the body has powerful therapeutic benefit and these cells have been routinely harvested for bone marrow transplantation to treat fatal leukemia and other hematologic disorders. Data from my laboratory suggests that the stem cells are actively going through cell division, rather than existing primarily in a resting state. We think this cycling behavior will profoundly impact how stem cells function and how they are purified for study. We have shown that this population of cycling stem cells is lost during the standard processes used to purify stem cells. Our goal is to explore this under-studied stem cell population of stem cells. We propose to more fully characterize these cells, their cell cycle status and function and determine how the process of going through cell division affects stem cell isolation and function. To do these experiments, we will harvest mouse bone marrow and then examine and manipulate mouse stem cells in vitro in order to study the effects of cell division on stem cell purification, engraftment function and differentiation. Overall, through this research, we hope to gain a better understanding of the total hematopoietic stem cell population. Our ultimate goal is to translate this information into improved strategies for purification and therapeutic utilizationof these crucial stem cells for the treatment of hematologic diseases.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
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NHLBI Mentored Clinical and Basic Science Review Committee (MCBS)
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Welniak, Lisbeth A
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Rhode Island Hospital
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Quesenberry, P; Goldberg, L (2017) A revisionist history of adult marrow stem cell biology or 'they forgot about the discard'. Leukemia 31:1678-1685
Aliotta, Jason M; Pereira, Mandy; Wen, Sicheng et al. (2017) Bone Marrow Endothelial Progenitor Cells Are the Cellular Mediators of Pulmonary Hypertension in the Murine Monocrotaline Injury Model. Stem Cells Transl Med 6:1595-1606
Wen, S; Dooner, M; Cheng, Y et al. (2016) Mesenchymal stromal cell-derived extracellular vesicles rescue radiation damage to murine marrow hematopoietic cells. Leukemia 30:2221-2231
Quesenberry, P J; Goldberg, L R (2015) Stem cell divisions and cancer. Leukemia 29:1959