Behavior of hematopoietic stem cells in a large animal.

Abkowitz, JL; Persik, Monica T.; Shelton, Grady H.; Ott, Richard L.; Kiklevich, J. Veronika; Catlin, Sandra N.; Guttorp, Peter

doi:10.1073/pnas.92.6.2031

Cited by 131 publications

(84 citation statements)

References 21 publications

(13 reference statements)

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“…BMT. The median interval between bone marrow transplant After 18-20 days of incubation wells were examined for and clonogenic analyses was 6 years (range [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20].…”

Section: Methodsmentioning

confidence: 99%

Deficient reconstitution of early progenitors after allogeneic bone marrow transplantation

Podestà

Piaggio

Frassoni

et al. 1997

Bone Marrow Transplant

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Summary:time required for stem cells to reconstitute sufficiently a large reservoir; later, hematopoiesis is maintained by the Allogeneic bone marrow transplant recipients maintain progeny of relatively few cells. 5 normal peripheral blood counts long term, suggestingLethally irradiated individuals engrafted with adequate durable support from engrafted stem cells. In order to numbers of allogeneic stem cells, achieve normal peripheral investigate late hemopoietic reconstitution at the level cell counts and good marrow cellularity in a short period of committed and early progenitors (LTC-IC), we studof time. 6,7 Recovery of committed progenitors is much ied 64 long-term survivors at a median interval of 6 slower and may remain permanently below the normal years (range: 2-20) after allogeneic bone marrow transrange 8,9 in patients with otherwise normal graft function. plant. CFU-GM and BFU-E numbers did not differThese data can be explained with a prolonged defect in the from normal controls; CFU-GEMM were found to be production of colony-forming cells (CFCs) from multisignificantly decreased (1.2 ؎ 0.2/10 5 vs 3.1 ؎ 0.4, potent and very early progenitors together with an impaired P ‫؍‬ 0.001). The most remarkable defect was however, or limited capacity of self-renewal of the latter 10 and an the low frequency of LTC-IC (3.2 ؎ 0.6/10 6 vs increased proportion of cells in cycle. 11,12 In addition, the 54.2 ؎ 9.3, P ‫؍‬ 0.0001) that did not improve with time host stromal microenvironment may be defective due to and did not correlate with phase of the disease, conexposure to chemotherapy and radiotherapy: in 58% of ditioning regimen, CMV infections or GVHD. Number patients studied after allogeneic bone marrow transplants, of infused cells and CFU-GM content of marrow grafts the stroma is considerably compromised in its ability to did not seem to influence the number of LTC-IC. This support early uncommitted hemopoietic cells and this study documents a significantly reduced number of defect lasts for several years. 13 These data are confirmed early progenitors in BMT patients despite normal numin patients transplanted with autologous marrow where bers of committed progenitors and normal peripheral difficulties or poor engraftment due to histocompatibility blood counts. This finding may suggest a permanent barriers can be excluded. 14 reduction of the stem cell reservoir after allogeneic boneThe information concerning the recovery of early and marrow transplantation.committed stem cell compartments in long-term survivors

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Section: Methodsmentioning

confidence: 99%

Deficient reconstitution of early progenitors after allogeneic bone marrow transplantation

Podestà

Piaggio

Frassoni

et al. 1997

Bone Marrow Transplant

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“…Less is known about HSC behavior in larger mammals or humans, in whom hematopoietic demand (ie, number of mature cells required) is significantly higher. To understand the adaptation to increased size and longevity, we have previously investigated HSC behavior in cats (which make the same number of red cells in 8 days as humans in 1 day or mice in a 2-year lifetime) 1 and have demonstrated that the frequencies of HSCs differ by 100-fold in mouse and cat marrow. [2][3][4][5][6][7][8] In this study, we determined the total number of HSCs.…”

Section: Introductionmentioning

confidence: 99%

Evidence that the number of hematopoietic stem cells per animal is conserved in mammals

Abkowitz

Catlin

McCallie

et al. 2002

Blood

210

175

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Humans and larger mammals require more blood cells per lifetime than mice because of their larger size and longer life expectancy. To investigate this evolutionary adaptation, we calculated the total number of nucleated marrow cells (NMCs) per cat, observing the distribution of 59 Fe to marrow, then multiplied this value (1.9 ؎ 0.9 ؋ 10 10 [mean ؎ SD]) times the frequency of feline hematopoietic stem cells (HSCs) (6 HSCs/10 7 NMCs) to derive the total number of HSCs per cat (11 400 ؎ 5400). Surprisingly, when the total number of HSCs per mouse was calculated with a similar experimental and computational approach, the value was equivalent. These data imply that the output of differentiated cells per feline HSC must vastly exceed that of murine HSCs. IntroductionHematopoietic stem cells (HSCs) are the functional units of blood cell production. Through self-renewal (replication) and differentiation, HSCs maintain hematopoiesis throughout an animal's lifetime. HSC number and kinetics have been studied extensively in mice and are genetically regulated. Less is known about HSC behavior in larger mammals or humans, in whom hematopoietic demand (ie, number of mature cells required) is significantly higher. To understand the adaptation to increased size and longevity, we have previously investigated HSC behavior in cats (which make the same number of red cells in 8 days as humans in 1 day or mice in a 2-year lifetime) 1 and have demonstrated that the frequencies of HSCs differ by 100-fold in mouse and cat marrow. [2][3][4][5][6][7][8] In this study, we determined the total number of HSCs. Surprisingly, it appears that the total number of HSCs in a cat is similar to, and within-estimation variability overlaps with, the total number of HSCs in a mouse. Study designTo compute the total number of HSCs in cats, HSC frequency (6 HSCs/10 7 nucleated marrow cells [NMCs] in adolescent cats, as determined by limiting-dilution competitive transplantation 6 ) was multiplied by the total number of NMCs. Because the number of NMCs per cat was unknown, the value was derived by observing the distribution of iron Fe 59 ( 59 Fe)-transferrin to the erythroid marrow of 4-to 9-month-old cats, using the methods of previous murine 7 and human 8 studies. In this way, a direct comparison of the results between species was feasible.In a preliminary study, we confirmed that 59 Fe had a t 1 ⁄2 in the circulation of 39 minutes. 9 We demonstrated that infused 59 Fe was undetectable in blood by 16 hours (which is 25 t 1 ⁄2 s), and we assumed complete redistribution to marrow at this time. Heparinized plasma (1.5-2.5 mL) was incubated with 3 Ci (0.111 MBq) 59 Fe as ferric chloride at 37°C for 30 minutes to allow transferrin saturation 9 and then was infused into cats intravenously. Studies were performed in 8 adolescent cats (4-to 10-monthold cats were used in studies to determine the HSC frequency 6 ). Marrow and blood were collected at baseline, 2 minutes after infusion, and at 16 to 23 hours. The number of NMCs and radioactivity (Auto-Gamma Coun...

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“…Moreover, a large fraction of murine PHSCs could be driven to self-replicate prior to their mobilization into the peripheral blood (PB) if stressed by the in vivo administration of cyclophosphamide and granulocyte-colony stimulating factor (G-CSF). 18 Since important differences are known to exist between the PHSCs of large animals and rodents, 19 we attempted to study PHSC quiescence during steady-state hematopoiesis and following stress induced by the administration of G-CSF. The studies were pursued owing to the uncertainty of whether the conclusions drawn from rodent experimentation could be used to further expand our understanding of human hematopoiesis.…”

Section: Introductionmentioning

confidence: 99%

“…This slow cycling behavior of baboon PHSCs is in agreement with the data generated by other researchers in other large animal models, including cats and rhesus macaques, and in humans. 13,19,[44][45][46][47][48] In particular, on the basis of measurements of telomere shortening in humans, Rufer et al 44 have previously reported that a rapid expansion of stem cells occurs early in life, followed by a marked decrease in the rate of stem cell divisions in the years that follow. They concluded that 15 to 30 stem cell divisions occur during the first half-year of life followed by less than 1 stem cell division per year in following years.…”

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confidence: 99%

The relative quiescence of hematopoietic stem cells in nonhuman primates

Mahmud

Devine

Weller

et al. 2001

Blood

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Quiescence has been thought to be required for the retention of the full biological potential of pluripotent hematopoietic stem cells (PHSCs). This hypothesis has been challenged recently by the observation that all murine PHSCs cycle continuously and constantly contribute to steadystate blood cell production. It was asked whether these observations could be extrapolated to describe hematopoiesis in higher mammals. In this series of experiments, the replicative history of PHSCs was examined in baboons by continuously administering bromodeoxyuridine (BrdU) for more than 85 weeks. The results indicate that under steady-state conditions, PHSCs remain largely quiescent but do cycle, albeit at a far lower rate than previously reported for rodent PHSCs. BrdU-labeled cycling PHSCs and progenitor cells were shown to have an extensive proliferative capacity and to contribute to blood cell production for prolonged periods of time. The proportion of PHSCs entering cell cycle could, however, be rapidly increased by the in vivo administration of granulocyte-colony stimulating factor. These data indicate that dur- IntroductionMammalian blood cell production is a tightly regulated process in which a hierarchy of cycling hematopoietic stem cell populations contributes to active hematopoiesis. [1][2][3][4][5] The formed elements of blood ultimately originate from rare pluripotent hematopoietic stem cells (PHSCs), which are capable of self-renewal and differentiation into cells belonging to each hematopoietic lineage. 6,7 PHSCs contribute to steady-state hematopoiesis and respond to a variety of stressful conditions without actually depleting their number. It is commonly believed that PHSCs remain quiescent during steady-state hematopoiesis and that stem cell quiescence plays a pivotal role in determining the self-renewal and proliferative potential of PHSCs. 8,9 In 1965, Kay 10 postulated that only a few PHSC clones actively contribute to blood cell production at any given time and that only after exhaustion of these active clones would additional PHSCs self-replicate and actively contribute to blood cell production. Experimental evidence supporting this clonal succession hypothesis was first gained by studies of the contribution of murine blood cell production by PHSCs that had been genetically modified by retroviral vectors. 11,12 The contribution of individual PHSCs to blood cell production was monitored by tracking retroviral integration sites in mature blood cells. Abkowitz and coworkers 13 also addressed this hypothesis by performing stem cell transplants in female cats who were heterozygotes for the X-linked gene glucose 6-phosphate dehydrogenase. They observed wide fluctuations in clonal contributions to hematopoiesis following initial engraftment but found that long-term reconstitution was due to a limited number of stem cell clones. 13 The validity of such reconstitution assays as an appropriate test of the clonal succession hypothesis has been questioned since the kinetics of hematopoietic reconstitution following st...

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Behavior of hematopoietic stem cells in a large animal.

Cited by 131 publications

References 21 publications

Deficient reconstitution of early progenitors after allogeneic bone marrow transplantation

Deficient reconstitution of early progenitors after allogeneic bone marrow transplantation

Evidence that the number of hematopoietic stem cells per animal is conserved in mammals

The relative quiescence of hematopoietic stem cells in nonhuman primates

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