Human hematopoietic stem cells from mobilized peripheral blood can be purified based on CD49f integrin expression

Huntsman, Heather D.; Bat, Taha; Cheng, Hai; Cash, Ayla; Cheruku, Patali S.; Fu, Junfen; Keyvanfar, Keyvan; Childs, Richard W.; Dunbar, Cynthia E.; Larochelle, André

doi:10.1182/blood-2015-07-660670

Cited by 27 publications

(21 citation statements)

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“…Panel C shows representative serial flow-cytometric analyses of phenotypically defined hematopoietic stem cells (HSCs; CD34+CD38–CD45RA–CD90+CD49f+ phenotype with low rhodamine uptake) in the bone marrow of Patient 29 and in a sample obtained from a healthy person (control). 21 Nucleated bone marrow cells were initially enriched for CD34+ cells by Magnetic Automated Cell Separation (MACS) and analyzed by means of flow cytometry for markers expressed on HSCs. Owing to the paucity of CD34+ cells at baseline, most of the cells that were measured had a CD34– phenotype.…”

Section: Figurementioning

confidence: 99%

Eltrombopag Added to Standard Immunosuppression for Aplastic Anemia

et al. 2017

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Background Acquired aplastic anemia results from immune-mediated destruction of bone marrow. Immunosuppressive therapies are effective, but reduced numbers of residual stem cells may limit their efficacy. In patients with aplastic anemia that was refractory to immunosuppression, eltrombopag, a synthetic thrombopoietin-receptor agonist, led to clinically significant increases in blood counts in almost half the patients. We combined standard immunosuppressive therapy with eltrombopag in previously untreated patients with severe aplastic anemia. Methods We enrolled 92 consecutive patients in a prospective phase 1–2 study of immunosuppressive therapy plus eltrombopag. The three consecutively enrolled cohorts differed with regard to the timing of initiation and the duration of the eltrombopag regimen (cohort 1 received eltrombopag from day 14 to 6 months, cohort 2 from day 14 to 3 months, and cohort 3 from day 1 to 6 months). The cohorts were analyzed separately. The primary outcome was complete hematologic response at 6 months. Secondary end points included overall response, survival, relapse, and clonal evolution to myeloid cancer. Results The rate of complete response at 6 months was 33% in cohort 1, 26% in cohort 2, and 58% in cohort 3. The overall response rates at 6 months were 80%, 87%, and 94%, respectively. The complete and overall response rates in the combined cohorts were higher than in our historical cohort, in which the rate of complete response was 10% and the overall response rate was 66%. At a median follow-up of 2 years, the survival rate was 97%; one patient died during the study from a nonhematologic cause. Marked increases in bone marrow cellularity, CD34+ cell number, and frequency of early hematopoietic progenitors were noted. Rates of relapse and clonal evolution were similar to our historical experience. Severe rashes occurred in two patients, resulting in the early discontinuation of eltrombopag. Conclusions The addition of eltrombopag to immunosuppressive therapy was associated with markedly higher rates of hematologic response among patients with severe aplastic anemia than in a historical cohort. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT01623167.)

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Section: Figurementioning

confidence: 99%

Eltrombopag Added to Standard Immunosuppression for Aplastic Anemia

et al. 2017

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“…While technology has improved so that it is now possible to isolate highly pure populations of human CD34 + CD38 − CD45RA − CD90 + HSCs from mobilized peripheral blood, purified primitive HSCs take a significantly longer time to engraft and reconstitute the hematopoietic system. The use of CD34 as a delineating marker for preparation of stem cells for transplantation must be considered carefully because it is expressed by other hematopoietic progenitors, including the MPP, common myeloid progenitor, B cell/NK cell progenitor, and the granulocyte–macrophage progenitor .…”

Section: Protocols Used In Human Hsc Transplantationmentioning

confidence: 99%

Targeting the Spleen as an Alternative Site for Hematopoiesis

et al. 2019

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Bone marrow is the main site for hematopoiesis in adults. It acts as a niche for hematopoietic stem cells (HSCs) and contains non‐hematopoietic cells that contribute to stem cell dormancy, quiescence, self‐renewal, and differentiation. HSC also exist in resting spleen of several species, although their contribution to hematopoiesis under steady‐state conditions is unknown. The spleen can however undergo extramedullary hematopoiesis (EMH) triggered by physiological stress or disease. With the loss of bone marrow niches in aging and disease, the spleen as an alternative tissue site for hematopoiesis is an important consideration for future therapy, particularly during HSC transplantation. In terms of harnessing the spleen as a site for hematopoiesis, here the remarkable regenerative capacity of the spleen is considered with a view to forming additional or ectopic spleen tissue through cell engraftment. Studies in mice indicate the potential for such grafts to support the influx of hematopoietic cells leading to the development of normal spleen architecture. An important goal will be the formation of functional ectopic spleen tissue as an aid to hematopoietic recovery following clinical treatments that impact bone marrow. For example, expansion or replacement of niches could be considered where myeloablation ahead of HSC transplantation compromises treatment outcomes.

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“…Wang et al [ 15 ] reported that about 1 in 400 adult BM 49f cells could engraft for at least 20 weeks. Huntsman et al [ 16 ] reported frequencies of engraftment of 49f cells purified from mobilized peripheral blood (PB) as high as 1 in 50 at eight weeks after transplantation, but did not report on the long-term outcome. Using a novel somatic transversion capture/recapture approach, Wang et al reported in 2020 that adult 49f cells could produce both myeloid and lymphoid cells for at least three years in adults [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Characterization of Hematopoiesis in Sickle Cell Disease by Prospective Isolation of Stem and Progenitor Cells

Tolu

Wang

Yan

et al. 2020

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The consequences of sickle cell disease (SCD) include ongoing hematopoietic stress, hemolysis, vascular damage, and effect of chronic therapies, such as blood transfusions and hydroxyurea, on hematopoietic stem and progenitor cell (HSPC) have been poorly characterized. We have quantified the frequencies of nine HSPC populations by flow cytometry in the peripheral blood of pediatric and adult patients, stratified by treatment and control cohorts. We observed broad differences between SCD patients and healthy controls. SCD is associated with 10 to 20-fold increase in CD34dim cells, a two to five-fold increase in CD34bright cells, a depletion in Megakaryocyte-Erythroid Progenitors, and an increase in hematopoietic stem cells, when compared to controls. SCD is also associated with abnormal expression of CD235a as well as high levels CD49f antigen expression. These findings were present to varying degrees in all patients with SCD, including those on chronic therapy and those who were therapy naive. HU treatment appeared to normalize many of these parameters. Chronic stress erythropoiesis and inflammation incited by SCD and HU therapy have long been suspected of causing premature aging of the hematopoietic system, and potentially increasing the risk of hematological malignancies. An important finding of this study was that the observed concentration of CD34bright cells and of all the HSPCs decreased logarithmically with time of treatment with HU. This correlation was independent of age and specific to HU treatment. Although the number of circulating HSPCs is influenced by many parameters, our findings suggest that HU treatment may decrease premature aging and hematologic malignancy risk compared to the other therapeutic modalities in SCD.

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Human hematopoietic stem cells from mobilized peripheral blood can be purified based on CD49f integrin expression

Cited by 27 publications

References 8 publications

Eltrombopag Added to Standard Immunosuppression for Aplastic Anemia

Eltrombopag Added to Standard Immunosuppression for Aplastic Anemia

Targeting the Spleen as an Alternative Site for Hematopoiesis

Characterization of Hematopoiesis in Sickle Cell Disease by Prospective Isolation of Stem and Progenitor Cells

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