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Hematopoietic stem cells count and remember their cell divisions throughout life
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Invited Speakers/ Experimental Hematology 44 (2016) S23–S38
1015 - HEMATOPOIETIC STEM CELLS COUNT AND REMEMBER THEIR CELL DIVISIONS THROUGHOUT LIFE Kateri Ann Moore1 and Jeffrey Bernitz2 1 Associate Professor, New York, USA; 2Icahn School of Medicine at Mount Sinai, New York, USA The ability of cells to count and remember their divisions could be key to aging, and disease. To date, a relationship between cellular memory and cell fate decisions has not been established. To investigate this phenomenon we tracked the cumulative divisional history of hematopoietic stem cells (HSCs) throughout adult life. Doing so revealed a rare fraction of HSCs that contained all the long-term repopulating HSC activity within the aging HSC compartment. We show that this population asynchronously undergoes symmetric self-renewal divisions during adult life, doubling its size with age, before entering into a state of permanent dormancy. Mathematical models demonstrate this expansion only occurs if each cell division results in progressive slowing of cell cycle initiation until reaching permanent dormancy after 4 divisions. Our results show that HSCs count and remember their divisional history. They also provide evidence that these phenomena may underlie HSC aging.
1016 - GENETIC BASIS OF THE EFFECTS OF BONE ON HEMATOPOIETIC AGING AND DISEASE Stavroula Kousteni1, Marshall Nakagawa2, and Ellin Berman3 1 Department of Physiology and Cellular Biophysics, Columbia University, New York, USA; 2Columbia University, New York City, USA; 3 Memorial Sloan Kettering Cancer Center, New York, USA Aging in hematopoiesis is associated with a shift in hematopoietic lineage differentiation, an increase in myeloid related to B-lymphoid output. More recently, it has been suggested that bone marrow stromal cells can induce hematopoietic stem cell (HSC) lineage shift and may also affect compromised HSC repopulation capacity and homing that are all associated with aging. In addition, aging is a major risk factor for AML and myelodysplasia (MDS), both conditions arising from disrupted hematopoiesis. In the bone marrow microenvironment, cells of the osteoblast lineage influence hematopoiesis by affecting selfrenewal, expansion and function of HSC. They have also been involved in the development of myeloid diseases. We have found that osteoblast ablation in mice recreates an aging-like deregulation of hematopoiesis characterized by increased myeloid and suppressed B-cell lineage. At 10 weeks of age, mice lacking osteobalsts showed normal marrow cellularity but an increase in the marrow hematopoietic stem and progenitor cell (HSPC) pool size, defined by Lin-Sca+c-Kit+ (LSK) cells, compared to WT littermates. The myeloid/monocytic cell population (CD11b+/Gr1+) increased, whereas B-lymphopoiesis and erythropoiesis were compromised. This magnitude of changes reflects, at minimum, age-related alterations in hematopoiesis with myeloid populations amplified by osteoblast ablation. Consistent with this contention, analysis of 9-month old mice showed that osteoblast ablation exacerbates the hematopoietic deregulation observed in 2 month-old animals by increasing the magnitude of changes in the LSK, myeloid, megakaryocyte/erythroid progenitors, erythroid and mature B-cell populations. Long term HSC progenitors increase whereas short-term ones decrease. In addition, early myeloid progenitors (GMPs), that were not affected in 2 month-old mice lacking osteoblasts, were 4-fold increased in the aged animals. Similar observations were obtained from the analysis of hematopoietic cell populations in older human subjects who show a decrease in osteoblast numbers and bone mass. Favoring of myeloid lineage expansion in older mice and with osteoblast ablation, also favored the development of AML. Taken together these observations are consistent with the hypothesis that niche composition plays a role in declining HSC function with age. They also provide a better understanding of the ontogeny of these events.
Invited Speakers/ Experimental Hematology 44 (2016) S23–S38
1015 - HEMATOPOIETIC STEM CELLS COUNT AND REMEMBER THEIR CELL DIVISIONS THROUGHOUT LIFE Kateri Ann Moore1 and Jeffrey Bernitz2 1 Associate Professor, New York, USA; 2Icahn School of Medicine at Mount Sinai, New York, USA The ability of cells to count and remember their divisions could be key to aging, and disease. To date, a relationship between cellular memory and cell fate decisions has not been established. To investigate this phenomenon we tracked the cumulative divisional history of hematopoietic stem cells (HSCs) throughout adult life. Doing so revealed a rare fraction of HSCs that contained all the long-term repopulating HSC activity within the aging HSC compartment. We show that this population asynchronously undergoes symmetric self-renewal divisions during adult life, doubling its size with age, before entering into a state of permanent dormancy. Mathematical models demonstrate this expansion only occurs if each cell division results in progressive slowing of cell cycle initiation until reaching permanent dormancy after 4 divisions. Our results show that HSCs count and remember their divisional history. They also provide evidence that these phenomena may underlie HSC aging.
1016 - GENETIC BASIS OF THE EFFECTS OF BONE ON HEMATOPOIETIC AGING AND DISEASE Stavroula Kousteni1, Marshall Nakagawa2, and Ellin Berman3 1 Department of Physiology and Cellular Biophysics, Columbia University, New York, USA; 2Columbia University, New York City, USA; 3 Memorial Sloan Kettering Cancer Center, New York, USA Aging in hematopoiesis is associated with a shift in hematopoietic lineage differentiation, an increase in myeloid related to B-lymphoid output. More recently, it has been suggested that bone marrow stromal cells can induce hematopoietic stem cell (HSC) lineage shift and may also affect compromised HSC repopulation capacity and homing that are all associated with aging. In addition, aging is a major risk factor for AML and myelodysplasia (MDS), both conditions arising from disrupted hematopoiesis. In the bone marrow microenvironment, cells of the osteoblast lineage influence hematopoiesis by affecting selfrenewal, expansion and function of HSC. They have also been involved in the development of myeloid diseases. We have found that osteoblast ablation in mice recreates an aging-like deregulation of hematopoiesis characterized by increased myeloid and suppressed B-cell lineage. At 10 weeks of age, mice lacking osteobalsts showed normal marrow cellularity but an increase in the marrow hematopoietic stem and progenitor cell (HSPC) pool size, defined by Lin-Sca+c-Kit+ (LSK) cells, compared to WT littermates. The myeloid/monocytic cell population (CD11b+/Gr1+) increased, whereas B-lymphopoiesis and erythropoiesis were compromised. This magnitude of changes reflects, at minimum, age-related alterations in hematopoiesis with myeloid populations amplified by osteoblast ablation. Consistent with this contention, analysis of 9-month old mice showed that osteoblast ablation exacerbates the hematopoietic deregulation observed in 2 month-old animals by increasing the magnitude of changes in the LSK, myeloid, megakaryocyte/erythroid progenitors, erythroid and mature B-cell populations. Long term HSC progenitors increase whereas short-term ones decrease. In addition, early myeloid progenitors (GMPs), that were not affected in 2 month-old mice lacking osteoblasts, were 4-fold increased in the aged animals. Similar observations were obtained from the analysis of hematopoietic cell populations in older human subjects who show a decrease in osteoblast numbers and bone mass. Favoring of myeloid lineage expansion in older mice and with osteoblast ablation, also favored the development of AML. Taken together these observations are consistent with the hypothesis that niche composition plays a role in declining HSC function with age. They also provide a better understanding of the ontogeny of these events.