scholarly journals Interferon gamma selectively inhibits very primitive CD342+CD38- and not more mature CD34+CD38+ human hematopoietic progenitor cells.

1994 ◽  
Vol 180 (3) ◽  
pp. 1177-1182 ◽  
Author(s):  
H W Snoeck ◽  
D R Van Bockstaele ◽  
G Nys ◽  
M Lenjou ◽  
F Lardon ◽  
...  
Keyword(s):  
Stem Cell ◽  
Progenitor Cells ◽  
Interferon Gamma ◽  
Bone Marrow Cells ◽  
Hematopoietic Progenitor Cells ◽  
Hematopoietic Progenitor ◽  
Ifn Gamma ◽  
Hematopoietic Stem ◽  
First Time ◽  
Dose Dependent

To assess the effects of interferon gamma (IFN-gamma) on very primitive hematopoietic progenitor cells, CD34(2+)CD38- human bone marrow cells were isolated and cultured in a two-stage culture system, consisting of a primary liquid culture phase followed by a secondary semisolid colony assay. CD34(2+)CD38- cells needed at least the presence of interleukin 3 (IL-3) and kit ligand (KL) together with either IL-1, IL-6, or granulocyte-colony-stimulating factor (G-CSF) in the primary liquid phase in order to proliferate and differentiate into secondary colony-forming cells (CFC). Addition of IFN-gamma to the primary liquid cultures inhibited cell proliferation and generation of secondary CFC in a dose-dependent way. This was a direct effect since it was also seen in primary single cell cultures of CD34(2+)CD38- cells. The proliferation of more mature CD34+CD38+ cells, however, was not inhibited by IFN-gamma, demonstrating for the first time that IFN-gamma is a specific and direct hematopoietic stem cell inhibitor. IFN-gamma, moreover, preserves the viability of CD34(2+)CD38- cells in the absence of other cytokines. IFN-gamma could, therefore, play a role in the protection of the stem cell compartment from exhaustion in situations of hematopoietic stress and may be useful as stem cell protecting agent against chemotherapy for cancer.

scholarly journals Interferon-gamma enhances factor-dependent myeloid proliferation of human CD34+ hematopoietic progenitor cells

Blood ◽  
1992 ◽  
Vol 79 (10) ◽  
pp. 2628-2635 ◽  
Author(s):  
C Caux ◽  
I Moreau ◽  
S Saeland ◽  
J Banchereau
Keyword(s):  
Growth Factor ◽  
Progenitor Cells ◽  
Interferon Gamma ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Bone Marrow Cells ◽  
Hematopoietic Progenitor Cells ◽  
Hematopoietic Progenitor ◽  
Ifn Gamma ◽  
Gm Csf

Abstract Numerous studies have shown that interferon-gamma (IFN gamma) inhibits the proliferative effects of colony-stimulating factors (CSFs) on human bone marrow cells. In the present study we investigated the effects of IFN gamma and other described inhibitory factors on the proliferation of highly purified CD34+ human hematopoietic progenitor cells (HPC) in response to recombinant CSFs. While transforming growth factor-beta (TGF beta) and IFN alpha were highly inhibitory, IFN gamma strongly potentiated interleukin-3 (IL-3) and, to a lesser extent, granulocyte- macrophage-CSF (GM-CSF) induced growth of CD34+ HPC. IFN gamma had no significant proliferative effect per se, and did not affect granulocyte- CSF (G-CSF)-dependent cell proliferation. Within 10 days the number of viable cells generated in the presence of IL-3 + IFN gamma was two times higher than in the presence of IL-3 alone. Limiting dilution analysis showed that IFN gamma acts directly on its target cell to increase the frequency of IL-3-responding cells without affecting the average size of the IL-3-dependent clones. Enhanced frequency of IL-3- and GM-CSF-responding cells was also observed in colony assays where the addition of IFN gamma increased by twofold to threefold the number of granulocyte colony-forming units (CFU-G), macrophage CFUs (CFU-M), granulocyte-macrophage CFUs (CFU-GM), and mixed erythroid (E-MIX). In contrast, IFN gamma did not affect the generation of erythroid burst- forming units (BFU-e) in such cultures. In longer-term culture, the combination of IFN gamma and IL-3 did not alter the lineage distribution of the cells when compared with IL-3 alone. However, after 15 days, when mature cells were present in the cultures, IFN gamma displayed cell concentration-related growth-inhibitory effects. Thus, IFN gamma appears to stimulate the early stage of myelopoiesis by enhancing the frequency of growth factor-responding cells but, unlike tumor necrosis factor alpha (TNF alpha), does not alter cell differentiation.

scholarly journals Interferon-gamma enhances factor-dependent myeloid proliferation of human CD34+ hematopoietic progenitor cells

Blood ◽  
1992 ◽  
Vol 79 (10) ◽  
pp. 2628-2635 ◽  
Author(s):  
C Caux ◽  
I Moreau ◽  
S Saeland ◽  
J Banchereau
Keyword(s):  
Growth Factor ◽  
Progenitor Cells ◽  
Interferon Gamma ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Bone Marrow Cells ◽  
Hematopoietic Progenitor Cells ◽  
Hematopoietic Progenitor ◽  
Ifn Gamma ◽  
Gm Csf

Numerous studies have shown that interferon-gamma (IFN gamma) inhibits the proliferative effects of colony-stimulating factors (CSFs) on human bone marrow cells. In the present study we investigated the effects of IFN gamma and other described inhibitory factors on the proliferation of highly purified CD34+ human hematopoietic progenitor cells (HPC) in response to recombinant CSFs. While transforming growth factor-beta (TGF beta) and IFN alpha were highly inhibitory, IFN gamma strongly potentiated interleukin-3 (IL-3) and, to a lesser extent, granulocyte- macrophage-CSF (GM-CSF) induced growth of CD34+ HPC. IFN gamma had no significant proliferative effect per se, and did not affect granulocyte- CSF (G-CSF)-dependent cell proliferation. Within 10 days the number of viable cells generated in the presence of IL-3 + IFN gamma was two times higher than in the presence of IL-3 alone. Limiting dilution analysis showed that IFN gamma acts directly on its target cell to increase the frequency of IL-3-responding cells without affecting the average size of the IL-3-dependent clones. Enhanced frequency of IL-3- and GM-CSF-responding cells was also observed in colony assays where the addition of IFN gamma increased by twofold to threefold the number of granulocyte colony-forming units (CFU-G), macrophage CFUs (CFU-M), granulocyte-macrophage CFUs (CFU-GM), and mixed erythroid (E-MIX). In contrast, IFN gamma did not affect the generation of erythroid burst- forming units (BFU-e) in such cultures. In longer-term culture, the combination of IFN gamma and IL-3 did not alter the lineage distribution of the cells when compared with IL-3 alone. However, after 15 days, when mature cells were present in the cultures, IFN gamma displayed cell concentration-related growth-inhibitory effects. Thus, IFN gamma appears to stimulate the early stage of myelopoiesis by enhancing the frequency of growth factor-responding cells but, unlike tumor necrosis factor alpha (TNF alpha), does not alter cell differentiation.

Oxidative Stress-Mediated Activation of AKT/mTOR Signaling Pathway Leads to Myeloproliferative Syndrome in FoxO3 Null Mice: A Role for Lnk Adaptor Protein

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 509-509 ◽  
Author(s):  
Safak Yalcin ◽  
Sathish Kumar Mungamuri ◽  
Dragan Marinkovic ◽  
Xin Zhang ◽  
Wei Tong ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Bone Marrow Cells ◽  
Ex Vivo ◽  
Hematopoietic Progenitor Cells ◽  
Cytokine Signaling ◽  
Wild Type ◽  
Hematopoietic Progenitors ◽  
Hematopoietic Progenitor ◽  
Hematopoietic Stem

Abstract Reactive oxygen species (ROS) are toxic byproducts of oxidative metabolism implicated in many debilitating human disorders including hematological malignancies and aging. ROS are also generated by growth factors and cytokine stimulation and play critical functions in normal cellular signaling. However, not much is known of how ROS impact physiological processes in normal and diseased states. We and others have recently shown critical functions for box (O) family of forkhead transcription factors (Fox)O in the regulation of physiological ROS in primitive hematopoietic cells. In particular, FoxO3 has emerged as the principal FoxO whose regulation of ROS is essential for the maintenance of hematopoietic stem cell pool. Although FoxO3’s activity is constitutively repressed by several oncoproteins that play critical roles in myeloproliferative disorders the role of FoxO3 in the regulation of primitive hematopoietic progenitors remains elusive. FoxO’s function is restrained by AKT serine threonine protein kinase. AKT supports growth, survival and proliferation by promoting inhibition of FoxO and activation of the mammalian target of rapamycin (mTOR) and its downstream target p70 S6 Kinase (S6K) through phosphorylation. We demonstrate that loss of FoxO3 leads to a myeloproliferative-like syndrome characterized by leukocytosis, splenomegaly, enhanced generation of primitive progenitors including colony-forming-unit-spleen (CFU-S) in hematopoietic organs and hypersensitivity of hematopoietic progenitor cells to cytokines in FoxO3 null mice. These findings were intriguing since we had not found FoxO3 null hematopoietic stem cells to exhibit enhanced cycling in vivo or to generate excessive hematopoietic progenitors ex vivo (Yalcin et al., JBC, 2008). To investigate the mechanism of enhanced myeloproliferation, we interrogated cytokine-mediated activation of signaling pathways in freshly isolated FoxO3 null versus wild type bone marrow cells enriched for hematopoietic progenitors. To our surprise we found that stimulation with cytokines including IL-3 led to hyperphosphorylation of AKT, mTOR and S6K but not STAT5 proteins in FoxO3 null as compared to wild type cytokine-starved hematopoietic progenitors. In agreement with these results, in vivo administration of the mTOR inhibitor rapamycin resulted in significant reduction of FoxO3 null- but not wild type-derived CFU-Sd12 in lethally irradiated hosts. These unexpected results suggested that AKT/mTOR signaling pathway is specifically overactivated as part of a feedback loop mechanism and mediates enhanced generation of FoxO3 null primitive multipotential hematopoietic progenitors in vivo. We further showed that phosphorylation of AKT/mTOR/S6K is highly sensitive to ROS scavenger N-Acetyl-Cysteine (NAC) in vivo and ex vivo in both wild type and FoxO3 null primitive hematopoietic progenitors indicating that ROS are involved in cytokine signaling in primary hematopoietic progenitor cells. Interestingly, in vivo administration of NAC normalized the number of FoxO3 null-derived CFU-Sd12 in lethally irradiated hosts without any impact on wild type CFU-Sd12 strongly suggesting that ROS mediate specifically enhanced generation of primitive hematopoietic progenitors in FoxO3 null mice. In this context, we were surprised to find similar levels of ROS concentrations in FoxO3 mutant as compared to control hematopoietic progenitors. Thus, we asked whether the increase in FoxO3 null primitive hematopoietic progenitor compartment is due to an increase sensitivity of cytokine signaling to ROS as opposed to increased ROS build up per se in these cells. In search for a mechanism we found the expression of Lnk, a negative regulator of cytokine signaling, to be highly reduced in FoxO3 null primitive hematopoietic progenitor cells. We further demonstrated that retroviral reintroduction of Lnk but not vector control in FoxO3 null primitive bone marrow cells reduced significantly the number of FoxO3 null-derived CFU-Sd12in vivo. Collectively, these results suggest that reduced expression of Lnk hypersensitizes FoxO3-deficient hematopoietic progenitors to ROS generated by cytokine signaling leading to myeloproliferation. These cumulative findings uncover a mechanism by which deregulation of cellular sensitivity to physiological ROS leads to hematopoietic malignancies specifically in disorders in which FoxO play a role.

scholarly journals Arhgap21 Expression in Bone Marrow Niche Is Crucial for Hematopoietic Progenitor Homing and Short Term Reconstitution after Transplantation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1591-1591
Author(s):  
Juliana M. Xavier ◽  
Lauremilia Ricon ◽  
Karla Priscila Vieira ◽  
Longhini Ana Leda ◽  
Carolina Bigarella ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Progenitor Cells ◽  
Peripheral Blood ◽  
Hematopoietic Progenitor Cells ◽  
Bone Marrow Niche ◽  
Wild Type ◽  
Hematopoietic Progenitor ◽  
Short Term ◽  
Hematopoietic Stem

Abstract The microenvironment of the bone marrow (BM) is essential for retention and migration of hematopoietic progenitor cells. ARHGAP21 is a negative regulator of RhoGTPAses, involved in cellular migration and adhesion, however the role of ARHGAP21 in hematopoiesis is unknown. In order to investigate whether downregulation of Arhgap21 in microenvironment modulates bone marrow homing and reconstitution, we generated Arhgap21+/-mice using Embryonic Stem cell containing a vector insertion in Arhgap21 gene obtained from GeneTrap consortium and we then performed homing and bone marrow reconstitution assays. Subletally irradiated (9.5Gy) Arhgap21+/- and wild type (WT) mice received 1 x 106 BM GFP+cells by IV injection. For homing assay, 19 hours after the transplant, Lin-GFP+ cells were analyzed by flow cytometry. In reconstitution and self-renew assays, the GFP+ cell percentage in peripheral blood were analyzed 4, 8, 12 and 16 weeks after transplantation. Hematopoietic stem cells [GFP+Lin-Sca+c-Kit+ (LSK)] were counted after 8 and 16 weeks in bone marrow after primary transplant and 16 weeks after secondary transplant. The percentage of Lin-GFP+ hematopoietic progenitor cells that homed to Arhgap21+/-recipient (mean± SD) (2.07 ± 0.85) bone marrow was lower than those that homed to the WT recipient (4.76 ± 2.60); p=0.03. In addition, we observed a reduction (WT: 4.22 ±1.39; Arhgap21+/-: 2.17 ± 0.69; p=0.001) of Lin- GFP+ cells in Arhgap21+/-receptor spleen together with an increase of Lin- GFP+ population in Arhgap21+/-receptor peripheral blood (WT: 8.07 ± 3.85; Arhgap21+/-: 14.07 ±5.20; p=0.01), suggesting that hematopoietic progenitor cells which inefficiently homed to Arhgap21+/-bone marrow and spleen were retained in the blood stream. In bone marrow reconstitution assay, Arhgap21+/-receptor presented reduced LSK GFP+ cells after 8 weeks (WT: 0.19 ±0.03; Arhgap21+/-0.12±0.05; p=0.02) though not after 16 weeks from primary and secondary transplantation. The reduced LSK percentage after short term reconstitution was reflected in the lower GFP+ cells in peripheral blood 12 weeks after transplantation (WT: 96.2 ±1.1; Arhgap21+/-94.3±1.6; p=0.008). No difference was observed in secondary transplantation, indicating that Arhgap21reduction in microenvironment does not affect normal hematopoietic stem cell self-renewal. The knowledge of the niche process in regulation of hematopoiesis and their components helps to better understand the disordered niche function and gives rise to the prospect of improving regeneration after injury or hematopoietic stem and progenitor cell transplantation. In previous studies, the majority of vascular niche cells were affected after sublethal irradiation, however osteoblasts and mesenchymal stem cells were maintained (Massimo Dominici et al.; Blood; 2009.). RhoGTPase RhoA, which is inactivated by ARHGAP21 (Lazarini et al.; Biochim Biophys acta; 2013), has been described to be crucial for osteoblasts and mesenchymal stem cell support of hematopoiesis (Raman et al.; Leukemia; 2013). Taken together, these results suggest that Arhgap21 expression in bone marrow niche is essential for homing and short term reconstitution support. Moreover, this is the first study to investigate the role of Arhgap21 in bone marrow niche. Figure 1 Reduced homing and short term reconstitution in Arhgap21 +/- recipients. Bone marrow cells from GFP+ mice were injected into wild-type and Arhgap21+/- sublethally irradiated mice. 19 hours after the transplant, a decreased homing was observed to both bone marrow (a) and spleen (b) together with an increase of retained peripheral blood (c) Lin-GFP+ cells. In serial bone marrow transplantation, Arhgap21+/- presented reduced bone marrow LSK GFP+ cells 8 weeks (d) and peripheral blood GFP+ cells 12 weeks (e) after primary transplantation, though not 16 weeks after primary (f) and 16 weeks after secondary (g) transplantations. The result is expressed by means ±SD of 2 independent experiments. Figure 1. Reduced homing and short term reconstitution in Arhgap21+/- recipients. Bone marrow cells from GFP+ mice were injected into wild-type and Arhgap21+/- sublethally irradiated mice. 19 hours after the transplant, a decreased homing was observed to both bone marrow (a) and spleen (b) together with an increase of retained peripheral blood (c) Lin-GFP+ cells. In serial bone marrow transplantation, Arhgap21+/- presented reduced bone marrow LSK GFP+ cells 8 weeks (d) and peripheral blood GFP+ cells 12 weeks (e) after primary transplantation, though not 16 weeks after primary (f) and 16 weeks after secondary (g) transplantations. The result is expressed by means ±SD of 2 independent experiments. Disclosures No relevant conflicts of interest to declare.

scholarly journals Hematopoietic stem cell transplantation alters susceptibility to pulmonary hypertension in Bmpr2-deficient mice

2018 ◽  
Vol 8 (4) ◽  
pp. 204589401880164 ◽  
Author(s):  
Alexi Crosby ◽  
Mark R. Toshner ◽  
Mark R. Southwood ◽  
Elaine Soon ◽  
Benjamin J. Dunmore ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Progenitor Cells ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Low Dose ◽  
Hematopoietic Progenitor Cells ◽  
Hematopoietic Progenitor ◽  
Hematopoietic Stem

Increasing evidence suggests that patients with pulmonary arterial hypertension (PAH) demonstrate abnormalities in the bone marrow (BM) and hematopoietic progenitor cells. In addition, PAH is associated with myeloproliferative diseases. We have previously demonstrated that low-dose lipopolysaccharide (LPS) is a potent stimulus for the development of PAH in the context of a genetic PAH mouse model of BMPR2 dysfunction. We hypothesized that the hematopoietic progenitor cells might be driving disease in this model. To test this hypothesis, we performed adoptive transfer of BM between wild-type (Ctrl) and heterozygous Bmpr2 null (Mut) mice. Sixteen weeks after BM reconstitution, mice were exposed to low-dose chronic LPS (0.5 mg/kg three times a week for six weeks). Mice underwent right heart catheterization and tissues were removed for histology. After chronic LPS dosing, Ctrl mice in receipt of Mut BM developed PAH, whereas Mut mice receiving Ctrl BM were protected from PAH. BM histology demonstrated an increase in megakaryocytes and there was an increase in circulating platelets in Ctrl mice receiving Mut BM. These findings demonstrate that the hematopoietic stem cell compartment is involved in the susceptibility to PAH in the Mut mouse. The results raise the possibility that hematopoietic stem cell transplantation might be a potential treatment strategy in genetic forms of PAH.

scholarly journals Functional activity of animal bone marrow cells after their treatment with nanocomplexes

2021 ◽  
Vol 29 (2) ◽  
pp. 9-21
Author(s):  
A. M. Goltsev ◽  
T. G. Dubrava ◽  
Yu. O. Gaevska ◽  
N. M. Babenko ◽  
M. O. Bondarovych ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Toxic Effect ◽  
Progenitor Cells ◽  
Functional Activity ◽  
Therapeutic Dose ◽  
Bone Marrow Cells ◽  
Earth Metal ◽  
Hematopoietic Progenitor Cells ◽  
National Academy Of Sciences ◽  
Hematopoietic Progenitor

Background. Previously, the antitumor activity of nanocomplexes (NCs) containing nanoparticles of rare earth metal orthovanadates GdYEuVO4 and cholesterol has been approved when applied in 9:1 ratio (the cells-to-NCs), which can be considered as a conditionally therapeutic dose. Therefore, studying the potential risks of NCs exposure in terms of functional activity of hematopoietic progenitor cells is relevant. Рurpose – determining a toxic effect of NCs on functional activity of hematopoietic cells of bone marrow (BM). Materials and Methods. The study was performed in BM cells of CBA/H mice. Nanocomplexes were synthesized at Institute for Scintillation Materials of the National Academy of Sciences of Ukraine. BM cells with NCs were incubated in the ratios as follows: 9BM:1NCs; 1BM:1NCs; 1BM:9NCs, followed by assessing the number of apoptotic/necrotic cells in BM using FITC Annexin V Apoptosis Detection Kit I (BD, USA) by means of “FACS Calibur” flow cytometer (“BD”, USA). Hematopoietic progenitor cells of BM were functionally evaluated in vivo by determining the content of colony-forming units of the spleen (CFUs) and the number of myelokaryocytes in lethally irradiated recipients on day 8 after administering BM cells, pre-incubated with NCs. Survival of irradiated recipient mice after BM administration was recorded 12 days long. Results and discussion. The dose-dependent effect of functional potential in- hibition for BM hematopoietic progenitor cells under NCs influence has been established. Although, in vitro processing the BM cells with a conditionally therapeutic dose of NCs (9BM:1NCs) before administration to irradiated animal caused remodeling of cell membranes and contributed to apoptotic manifes- tations, but it did not lead to strong changes in their colony-forming potential and did not reduce the number of BM cells in animals if compared with the introduced BM cells without NCs treatment. Increasing the NCs concentration five- and tenfold significantly reduced the colony-forming potential of BM cells, caused BM hypoplasia and a crucial reduction in the survival of recipient animals, indicating possible toxic effects of this compound when administered at high concentrations. Conclusions. The toxic effect of NCs is detected only when certain concen- trations, significantly exceeding the conditionally therapeutic dose previously determined when treating the experimental oncology diseases, are used.

scholarly journals Identification of BCR/ABL-negative primitive hematopoietic progenitor cells within chronic myeloid leukemia marrow

Blood ◽  
1993 ◽  
Vol 81 (3) ◽  
pp. 801-807 ◽  
Author(s):  
T Leemhuis ◽  
D Leibowitz ◽  
G Cox ◽  
R Silver ◽  
EF Srour ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Chronic Myeloid Leukemia ◽  
Progenitor Cells ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Polymerase Chain Reaction Analysis ◽  
Hematopoietic Progenitor Cells ◽  
Hematopoietic Progenitor ◽  
Hematopoietic Stem

Chronic myeloid leukemia (CML) is a malignant disorder of the hematopoietic stem cell. It has been shown that normal stem cells coexist with malignant stem cells in the bone marrow of patients with chronic-phase CML. To characterize the primitive hematopoietic progenitor cells within CML marrow, CD34+DR- and CD34+DR+ cells were isolated using centrifugal elutriation, monoclonal antibody labeling, and flow cytometric cell sorting. Polymerase chain reaction analysis of RNA samples from these CD34+ subpopulations was used to detect the presence of the BCR/ABL translocation characteristic of CML. The CD34+DR+ subpopulation contained BCR/ABL(+) cells in 11 of 12 marrow samples studied, whereas the CD34+DR- subpopulation contained BCR/ABL(+) cells in 6 of 9 CML marrow specimens. These cell populations were assayed for hematopoietic progenitor cells, and individual hematopoietic colonies were analyzed by PCR for their BCR/ABL status. Results from six patients showed that nearly half of the myeloid colonies cloned from CD34+DR- cells were BCR/ABL(+), although the CD34+DR- subpopulation contained significantly fewer BCR/ABL(+) progenitor cells than either low-density bone marrow (LDBM) or the CD34+DR+ fraction. These CD34+ cells were also used to establish stromal cell-free long-term bone marrow cultures to assess the BCR/ABL status of hematopoietic stem cells within these CML marrow populations. After 28 days in culture, three of five cultures initiated with CD34+DR- cells produced BCR/ABL(-) cells. By contrast, only one of eight cultures initiated with CD34+DR+ cells were BCR/ABL(-) after 28 days. These results indicate that the CD34+DR- subpopulation of CML marrow still contains leukemic progenitor cells, although to a lesser extent than either LDBM or CD34+DR+ cells.

The histone lysine acetyltransferase HBO1 (KAT7) regulates hematopoietic stem cell quiescence and self-renewal

Blood ◽  
2021 ◽  
Author(s):  
Yuqing Yang ◽  
Andrew J Kueh ◽  
Zoe Grant ◽  
Waruni Abeysekera ◽  
Alexandra L Garnham ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Progenitor Cells ◽  
Hematopoietic Stem Cell ◽  
Cell Function ◽  
Bone Marrow Cells ◽  
High Rate ◽  
Embryonic Patterning ◽  
Self Renewal ◽  
Hematopoietic Stem

The histone acetyltransferase HBO1 (MYST2, KAT7) is indispensable for postgastrulation development, histone H3 lysine 14 acetylation (H3K14Ac) and the expression of embryonic patterning genes. In this study, we report the role of HBO1 in regulating hematopoietic stem cell function in adult hematopoiesis. We used two complementary cre-recombinase transgenes to conditionally delete Hbo1 (Mx1-Cre and Rosa26-CreERT2). Hbo1 null mice became moribund due to hematopoietic failure with pancytopenia in the blood and bone marrow two to six weeks after Hbo1 deletion. Hbo1 deleted bone marrow cells failed to repopulate hemoablated recipients in competitive transplantation experiments. Hbo1 deletion caused a rapid loss of hematopoietic progenitors (HPCs). The numbers of lineage-restricted progenitors for the erythroid, myeloid, B-and T-cell lineages were reduced. Loss of HBO1 resulted in an abnormally high rate of recruitment of quiescent hematopoietic stem cells (HSCs) into the cell cycle. Cycling HSCs produced progenitors at the expense of self-renewal, which led to the exhaustion of the HSC pool. Mechanistically, genes important for HSC functions were downregulated in HSC-enriched cell populations after Hbo1 deletion, including genes essential for HSC quiescence and self-renewal, such as Mpl, Tek(Tie-2), Gfi1b, Egr1, Tal1(Scl), Gata2, Erg, Pbx1, Meis1 and Hox9, as well as genes important for multipotent progenitor cells and lineage-specific progenitor cells, such as Gata1. HBO1 was required for H3K14Ac through the genome and particularly at gene loci required for HSC quiescence and self-renewal. Our data indicate that HBO1 promotes the expression of a transcription factor network essential for HSC maintenance and self-renewal in adult hematopoiesis.

scholarly journals Gene transfer into hematopoietic progenitor cells from normal and cyclic hematopoietic dogs using retroviral vectors

Blood ◽  
1988 ◽  
Vol 71 (3) ◽  
pp. 717-722 ◽  
Author(s):  
MA Eglitis ◽  
PW Kantoff ◽  
JD Jolly ◽  
JB Jones ◽  
WF Anderson ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Bone Marrow Cells ◽  
Retroviral Vectors ◽  
Hematopoietic Progenitor Cells ◽  
Neomycin Phosphotransferase ◽  
Drug Resistant ◽  
Hematopoietic Progenitor ◽  
Exogenous Genes ◽  
Murine Leukemia

Abstract The Moloney murine leukemia retrovirus-derived vector N2 was used to transfer the bacterial NeoR gene (conferring resistance to the neomycin analogue G418) into hematopoietic progenitor cells. Approximately 5% of day seven CFU-GM were resistant to 2,000 micrograms/ml G418, using a supernatant infection protocol in the absence of vector-producing cells. A greater proportion of CFU-GM colonies were recovered relative to uninfected controls as the stringency of selection was diminished. Enzyme activity was detected in drug-resistant colonies, confirming that the resistant colonies obtained after infection with N2 represented cells producing neomycin phosphotransferase. Activity in the CFU-GM colonies approached 50% of that of drug-resistant vector- producing cells on a per cell basis. To test the hypothesis that more rapidly cycling bone marrow cells would be more susceptible to vector infection, we treated progenitor cells obtained from cyclic hematopoietic (CH) dogs with the N2 vector. Despite the increased numbers of hematopoietic progenitor cells obtained from CH dogs, the proportion of G418-resistant CFU-GM did not increase over that obtained with N2-infected normal marrow. These results demonstrate that retroviral vectors can be used to transfer and express exogenous genes in canine hematopoietic progenitor cells.

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