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PubMed1997

HLA-DR-mediated signals for hematopoiesis and induction of apoptosis involve but are not limited to a nitric oxide pathway.

Cross-linking of major histocompatibility complex (MHC) class II antigens by anti-HLA-DR monoclonal antibody (MoAb; H81.9; IgG2a) results in inhibition of hematopoiesis in canine and human models. Inhibition of hematopoiesis is associated with apoptosis in a proportion of marrow cells. Since in murine macrophages class II cross-linking triggers nitric oxide (NO) production, and NO is thought to affect regulation of hematopoiesis, we investigated whether NO was involved in our models. In murine J774 monocytes/macrophages, MoAb H81.9 did induce NO. NO production was blocked by N(G)-monomethyl-L-arginine (NMMA), an inhibitor of NO synthase (NOS), and by the antioxidant N-acetylcysteine (NAC). In human and canine long-term marrow cultures (LTMCs) and in enriched marrow monocytes, however, no measurable increase in NO production was noted after H81.9 exposure. Nevertheless, NAC protected LTMCs against H81.9 induced inhibition of hematopoiesis. Therefore, we determined the effect of an exogenous NO donator, sin-1 (3-morpholinosydnonimine), on canine and human LTMCs and on apoptosis. Sin-1 at concentrations > or =100 microg/mL inhibited LTMCs and induced apoptosis; at low concentrations (1 microg/mL), however, sin-1 stimulated the generation of colony-forming unit granulocyte-macrophage. Combined treatment with sin-1 at 100 microg/mL and MoAb H81.9 resulted in profound inhibition of hematopoiesis in both canine and human LTMCs, and had an additive effect on apoptosis. At 1 microg/mL sin-1 counteracted the effect of H81.9 on hematopoiesis. The effect of sin-1 on apoptosis and hematopoiesis in LTMC was largely prevented by NAC. These results are consistent with the hypothesis that HLA-DR mediated apoptosis and inhibition of hematopoiesis involve oxidative stress. However, the biphasic response of hematopoiesis to sin-1 suggests a complex regulatory network possibly related to differences in NO sensitivity of distinct subpopulations of cells. Signals in addition to NO appear to be involved in the effect of anti-HLA-DR MoAb on hematopoiesis.

Animals↗

PubMed2004

[Ontogenesis of the renin system. Implication of this system in hematopoiesis].

The role of the renin-angiotensin system was previously thought to be restricted to the cardiovascular system. It now appears that this system also plays an important role during development, and especially in hematopoiesis. The different elements of the renin-angiotensin system are expressed early during embryogenesis. The renin system plays a role at different steps of hematopoiesis, notably during the first wave of hematopoiesis in the chick embryo system (primitive hematopoiesis), and during the adult phase of hematopoiesis in the fetus (definitive hematopoiesis). In addition, this system is involved in hematopoiesis following experimental irradiation of mice: renin system antagonists improve hematopoiesis in this situation.

Angiotensin II↗

PubMed2002

[Extramedullary hematopoiesis in the paravertebral space].

BACKGROUND: Extramedullary hematopoiesis is a response of the organism to a deficient production of blood-forming cells within the bone marrow. It may coincide with some hematologic diseases. Two patients with paravertebral mass lesions representing extramedullary hematopoiesis are discussed. Characteristic findings of extramedullary hematopoiesis are presented along with a review of the literature on this topic. CASE REPORTS: A 76-year-old male with a known myelodysplastic syndrome presented with pneumonia. In addition, he had symptoms of a cauda equina syndrome with complaints of pain and hypesthesia of the lower limbs as well as urinary retention. A 63-year-old female presented with aggravated complaints of the lower thorax, low back pain radiating to the upper left leg, and dysesthesia of both feet. In her past medical history, she had polycythemia vera and a splenectomy. Both patients showed paravertebral and intraspinal lesions located in the thoracic and sacral spine which were regarded as extramedullary hematopoiesis according to the imaging findings in MRI and CT. Radiation therapy showed marked improvement in their neurologic complaints following the initial sessions. CONCLUSION: Clinical presentation, knowledge of the underlying disease and of imaging findings are essential in the diagnosis of extramedullary hematopoiesis. MRI is the imaging modality of choice in the primary diagnosis of extramedullary hematopoiesis. Possible extension of the disease into the intraspinal space can be evaluated with high accuracy and differential diagnosis can be facilitated. In addition, MRI is of use in the accurate planning of radiation fields as well as during follow-up of extramedullary hematopoiesis.

Aged↗

PubMed2000

VEGF-C signaling pathways through VEGFR-2 and VEGFR-3 in vasculoangiogenesis and hematopoiesis.

Signaling by vascular endothelial growth factors (VEGFs) through VEGF receptors (VEGFRs) plays important roles in vascular development and hematopoiesis. The authors analyzed the function of VEGF-C signaling through both VEGFR-2 and VEGFR-3 in vasculoangiogenesis and hematopoiesis using a coculture of para-aortic splanchnopleural mesoderm (P-Sp) explants from mouse embryos with stromal cells (OP9). Vasculogenesis and angiogenesis were evaluated by the extent of vascular bed and network formation, respectively. Addition of VEGF-C to the P-Sp culture enhanced vascular bed formation and suppressed definitive hematopoiesis. Both vascular bed and network formations were completely suppressed by addition of soluble VEGFR-1-Fc competitor protein. Formation of vascular beds but not networks could be rescued by VEGF-C in the presence of the competitor, while both were rescued by VEGF-A. VEGFR-3-deficient embryos show the abnormal vasculature and severe anemia. Consistent with these in vivo findings, vascular bed formation in the P-Sp from the VEGFR-3-deficient embryos was enhanced to that in wild-type or heterozygous embryos, and hematopoiesis was severely suppressed. When VEGFR-3-Fc chimeric protein was added to trap endogenous VEGF-C in the P-Sp culture of the VEGFR-3-deficient embryos, vascular bed formation was suppressed and hematopoiesis was partially rescued. These results demonstrate that because VEGF-C signaling through VEGFR-2 works synergistically with VEGF-A, the binding of VEGF-C to VEGFR-3 consequently regulates VEGFR-2 signaling. In VEGFR-3-deficient embryos, an excess of VEGF-C signals through VEGFR-2 induced the disturbance of vasculogenesis and hematopoiesis during embryogenesis. This indicates that elaborated control through VEGFR-3 signaling is critical in vasculoangiogenesis and hematopoiesis. (Blood. 2000;96:3793-3800)

Animals↗

PubMed1996

Early ontogeny of the human marrow from long bones: an immunohistochemical study of hematopoiesis and its microenvironment.

We examined long bones from 42 human embryos and fetuses whose gestational ages ranged from 6 to 28 weeks. Bone rudiment sections were stained using a panel of monoclonal antibodies directed at antigens expressed by hematopoietic cells, endothelial cells, smooth muscle cells, fibro-blasts, and stromal cells, to describe the events preceding and accompanying the onset of hematopoiesis in the diaphyseal region. Five distinct stages were identified. Stage I (6.6 to 8.5 gestational weeks [gw]) was that of entirely cartilaginous rudiments: chondrocytes were dilated and capillaries with CD34+ endothelial cells were observed in the perichondral limb mesenchyme. At stage II (8.5-9 gw) chondrolysis was actively proceeding; numerous CD68+ cells were observed, interspersed within the marrow cavity. Stage III (9 to 10.5 gw) was characterized by the development of the vascular bed in the absence of detectable hematopoiesis. At mid-diaphysis, specific structures that we named primary logettes were discernible; they consisted of small chambers of connective tissue, framed by a loose network of CD45-negative cells organized around an arteriole and limited from the surrounding sinus by a clearcut lining of CD34+ endothelial cells flanked on their abluminal side by alpha SM actin+ myoid cells. Stage IV (10.5-15 gw) was characterized by the onset of hematopoiesis. Hematopoietic cells were found exclusively in the primary logettes that had considerably increased in size. Logettes filled with hematopoietic cells were immersed within large and almost empty vascular sinuses. Logettes were attached by a short pedicle to connective tissue adjacent to bone/cartilage remaining formations; this tissue contained very rare hematopoietic cells. Logettes were few, usually less than 10 per long bone, and found solely in the diaphyseal area. Most hematopoietic cells found inside logettes were CD15+ myelocytes; rarely seen were glycophorin A+ immature erythroblasts and CD34+ nonendothelial cells. Hematopoietic cells within the logettes were in contact with alpha SM actin+ myoid cells and flattened endothelial-like (although consistently CD34-negative), aligned cells limiting small capillary lumina. Stage V (16 gw onward) was that of final organization of the long bones with areas of fully calcified bone and areas of dense hematopoiesis where logettes were no longer visible. This study shows three major features of incipient long bone hematopoiesis: 1) absence of CD34+ hematopoietic precursors before the onset of hematopoiesis and extreme rarity of those in the emerging blood-forming marrow, 2) predominance of granulopoiesis, and 3) exclusive development in specific structures organized by vascular cells. This study also suggests that CD68+ cells are instrumental in the chondrolysis process while vascular cells (endothelial and myoid cells) may be the critical microenvironment at the onset of hematopoiesis.

Antigens, CD↗

PubMed1989

Differential induction of hematopoiesis and immune suppressor cells in the bone marrow versus in the spleen by Lewis lung carcinoma variants.

Mice bearing large (greater than or equal to 3 g) metastatic and nonmetastatic Lewis lung carcinoma (LLC) tumors were studied to determine if the tumor variants differentially induced bone marrow versus splenic hematopoiesis and the appearance of hematopoiesis-associated immune suppressor cells. The metastatic LLC-C3 and nonmetastatic LLC-C8 tumors were equal in their stimulatory effects in vivo on both the number of bone marrow myeloid progenitor cells (CFU) and the appearance of bone marrow immune suppressor cells. In contrast, the tumor variants differed in their effects on the spleen, with the metastatic tumors causing a more pronounced increase in the number of nucleated cells and CFU, a reduced blastogenic responsiveness to concanavalin (Con-A), and an increased suppressor cell activity than nonmetastatic LLC-C8 tumors. The splenic suppressor cells of mice bearing large LLC-C3 tumors resembled the bone marrow suppressor cells which we previously described (Young et al.: Cancer Res. 47, 100, 1987) in that they were nonadherent to nylon wool, sensitive to treatment with L-leucine methyl ester, insensitive to treatment with complement and Thy-1.2, MG-1.2, asialo-GM1, or anti-IgM antibodies, and mediated their suppression through a mechanism which was only partially indomethacin sensitive. The stimulatory effects on hematopoiesis and suppressor cells by the LLC variant tumors may have been mediated by the tumor-derived colony stimulating factor (CSF) activities. Bone marrow cell proliferation and colony formation were stimulated in vitro by culture supernatants of metastatic LLC-C3 cells and, to a lesser degree, of nonmetastatic LLC-C8 cells. These colony-stimulating factor (CSF)-containing supernatants also induced normal bone marrow cells to become immune suppressive. In contrast, supernatants of only LLC-C3 cells, and not of LLC-C8 cells, stimulated in vitro growth of splenic CFU from LLC-C3-bearing mice; spleen cells from normal mice and from LLC-C8 bearers were unresponsive to supernatants of the LLC variants. These results suggest that CSF produced by either the metastatic LLC-C3 or the nonmetastatic LLC-C8 tumors could concurrently stimulate bone marrow hematopoiesis and the appearance of bone marrow suppressor cells. However, the metastatic LLC-C3 tumor cells, and not the nonmetastatic LLC-C8 cells, could also cause expansion of progenitor cells and hematopoiesis to the spleen and, consequently, induce the appearance in the spleen of hematopoiesis-associated immune suppressor cells.

Animals↗

PubMed1999

In vivo disturbance of hematopoiesis in mice persistently infected with murine cytomegalovirus: impairment of stromal cell function.

Although the pathogenic effects of a primary cytomegalovirus (CMV) infection on hematopoiesis has been largely investigated so far, the effects of a persistent or latent infection have yet to be elucidated. The effects of persistent CMV infection on hematopoiesis thus were examined using BALB/c mice at 4 weeks postinfection with 0. 2 LD50 of murine CMV (MCMV) infection as a persistent infection model. The parameters of constitutive hematopoiesis of MCMV persistently infected mice were completely identical to those of the control. However, the inductive hematopoiesis, examined by the autologous marrow reconstitution after 5-fluorouracil administration, was significantly impaired in the MCMV persistently infected mice (P < 0.05). In a colony-forming unit-spleen assay and a long-term bone marrow culture system, a decreased capacity of bone marrow stromal cells to support hematopoiesis was observed in the MCMV-infected mice in comparison with the controls. The existence of MCMV DNA in the adherent cells of long-term bone marrow culture from the MCMV-infected mice were confirmed by a polymerase chain reaction but not in the nonadherent cells. Furthermore, the increased expression level of tumor necrosis factor-alpha by stromal cells was also observed by semiquantitative reverse transcriptase-polymerase chain reaction. These results therefore strongly suggest that MCMV remains to infect the stromal cells while also inhibiting inductive hematopoiesis through the impairment of the stromal cell functions in the MCMV persistently infected mice.

Animals↗

PubMed2005

Role of VLA-4 and VLA-5 in ex vivo maintenance of human and pig hematopoiesis in human stroma-supported long-term cultures.

OBJECTIVE: The advantage of recipient hematopoiesis over that of xenogeneic donors poses a fundamental obstacle to the induction of xenograft tolerance through mixed hematopoietic chimerism. Here we explore the role of beta1 integrins in maintenance of human vs porcine hematopoiesis within a human hematopoietic environment. METHODS: Porcine and human c-kit+ bone marrow cells were purified and cultured on human bone marrow stroma for 6 weeks. The role of VLA-4 and VLA-5 in the maintenance of porcine vs human hematopoiesis in this human stroma-supported long-term bone marrow culture (LTBMC) system was evaluated by using blocking mAbs that bind to both species. RESULTS: Blocking VLA-4 with HP2/1 inhibited both human and porcine hematopoiesis, whereas anti-VLA-5 (SAM-1) suppressed the function of human, but not porcine, hematopoietic cells. In mixed LTBMC of porcine and human cells on a human stroma, porcine hematopoietic cells were at a competitive disadvantage, as seen by a rapid decline in cellularity, including clonogenic progenitors. This disadvantage was substantially overcome by the addition of SAM-1. Furthermore, human, but not porcine, cell adhesion to human fibronectin was inhibited by arginine-glycine-aspartic acid (RGD) peptides. CONCLUSION: Taken together, these results indicate that VLA-4 plays critical role for porcine hematopoiesis in a human hematopoietic environment, and raise the possibility that porcine VLA-5 might be unable to bind the respective human ligand and/or to initiate adequate post-ligand-binding signaling. Thus, VLA-5 may provide a potential target for developing approaches to improve porcine hematopoiesis in human recipients.

Animals↗

PubMed2005

Posttransplant hematopoiesis in patients undergoing sibling allogeneic stem cell transplantation reflects that of their respective donors although with a lower functional capability.

We tested the principle of whether patient long-term hematopoiesis following allogeneic stem cell transplantation (allo-SCT) reflects the characteristics of the hematopoiesis of their respective donor. For this purpose, we analyzed bone marrow (BM) hematopoiesis using long-term cultures (LTC), delta assays, and clonogeneic assays as well as CD34+ cells and their subsets by flow cytometry in a series of 37 patients undergoing allo-SCT, and we compared it to that of their respective human leukocyte antigen-matched sibling donors in a paired study performed more than 1 year after the transplant procedure. Interestingly, the main factor that influenced post-allo-SCT BM hematopoiesis in the long term was donor hematopoiesis. Nevertheless, compared to their respective donors, patients exhibited a significantly lower number of colony-forming units granulomonocytic, burst-forming units erythroid, and immature progenitors (CD34++/CD38dim/CD90+/CD133+ cells, LTC-initiating cells, and colonies generated in the delta assay). Moreover, BM stromal function was diminished in patients undergoing allo-SCT compared to their donors. In addition, the presence of chronic graft-versus-host disease under immunosuppressive treatment also conditioned an impaired hematopoietic function. In summary, our study shows that BM hematopoiesis evaluated more than 1 year after an allo-SCT mainly reproduces that of their respective donors, although with a significantly decreased in vitro activity.

Adolescent↗

PubMed2001

Role of the microenvironment of the embryonic aorta-gonad-mesonephros region in hematopoiesis.

Although various cytokines, growth factors, and chemokines are known to regulate hematopoiesis, expansion of hematopoietic stem cells (HSCs) in vitro with the use of such agents has proved problematic. Stromal cells are major components of the microenvironment that surrounds hematopoietic cells and are thought to play an important role in hematopoiesis in vivo. Co-culture of HSCs with stromal cells promotes hematopoiesis and self-renewal of HSCs. Definitive hematopoietic cells first appear during mammalian embryonic development in the aorta-gonad-mesonephros (AGM) region, and it is therefore thought that the microenvironment of this region plays an important role in HSC ontogeny. We have adopted two approaches to studying the contribution of the AGM microenvironment to hematopoiesis. In the first approach, we have developed an in vitro culture system for mouse AGM explants. Hematopoiesis is enhanced in such cultures by the presence of the combination of stem cell factor (SCF), basic fibroblast growth factor, leukemia inhibitory factor, and oncostatin M (SFLO culture). However, transplantation assays revealed that HSCs capable of long-term reconstitution of the hematopoietic compartment of irradiated mice (LTR-HSCs) do not expand in AGM-SFLO cultures; rather, these cultures appear to provide a favorable microenvironment for hematogenic angioblasts that are precursors of both endothelial and hematopoietic cells. In our second approach, we have established various stromal cell lines from the mouse AGM region. The AGM-S3 cell line supports human and mouse primitive hematopoietic cells as well as mouse LTR-HSCs. Maintenance of LTR-HSCs is mediated by a mechanism other than SCF signaling through its receptor (c-Kit). These two in vitro approaches should prove useful for further elucidation of the mechanisms that underlie hematopoiesis and HSC self-renewal.

Animals↗

PubMed2004

Normal hematopoiesis is maintained by activated bone marrow CD4+ T cells.

CD4(+) T cells produce hematopoietic-related cytokines and are essential for hematopoiesis stimulation during infection and hematologic recovery after bone marrow transplantation. However, it remains unclear if T cells are necessary to maintain normal hematopoiesis. We report here that, in T-cell-deficient mice, terminal differentiation of myeloid progenitors is defective, resulting in very low levels of granulocytes in the periphery. Hematopoiesis is restored after thymus graft or reconstitution with CD4(+) T cells but not CD8(+) T cells. Bone marrow CD4(+) T cells have an activated phenotype and produce cytokines, apparently, in the absence of exogenous stimulation. Transgenic mice carrying T-cell receptor specific for an ovalbumin peptide presented in the context of a specific class II molecule (I-A(d)) (DO11.10 RAG(-/-)) show the same hematopoietic deficiency as athymic mice. Their bone marrow CD4(+) T cells are not activated, suggesting that hematopoiesis maintenance requires the presence of cognate antigen in order to activate bone marrow T-helper cells. In fact, priming of transgenic mice with ovalbumin restores normal hematopoiesis. The data show that the current concept of "normal hematopoiesis" does not reflect a basal bone marrow activity, but it is an antigen-induced state maintained by constant activation of bone marrow CD4(+) T cells.

Animals↗

PubMed2001

Core-binding factor beta (CBFbeta), but not CBFbeta-smooth muscle myosin heavy chain, rescues definitive hematopoiesis in CBFbeta-deficient embryonic stem cells.

Core-binding factor beta (CBFbeta) is the non-DNA-binding subunit of the heterodimeric CBFs. Genes encoding CBFbeta (CBFB), and one of the DNA-binding CBFalpha subunits, Runx1 (also known as CBFalpha2, AML1, and PEBP2alphaB), are required for normal hematopoiesis and are also frequent targets of chromosomal translocations in acute leukemias in humans. Homozygous disruption of either the Runx1 or Cbfb gene in mice results in embryonic lethality at midgestation due to hemorrhaging in the central nervous system, and severely impairs fetal liver hematopoiesis. Results of this study show that Cbfb-deficient mouse embryonic stem (ES) cells can differentiate into primitive erythroid colonies in vitro, but are impaired in their ability to produce definitive erythroid and myeloid colonies, mimicking the in vivo defect. Definitive hematopoiesis is restored by ectopic expression of full-length Cbfb transgenes, as well as by a transgene encoding only the heterodimerization domain of CBFbeta. In contrast, the CBFbeta-smooth muscle myosin heavy chain (SMMHC) fusion protein generated by the inv(16) associated with acute myeloid leukemias (M4Eo) cannot rescue definitive hematopoiesis by Cbfb-deficient ES cells. Sequences responsible for the inability of CBFbeta-SMMHC to rescue definitive hematopoiesis reside in the SMMHC portion of the fusion protein. Results also show that the CBFbeta-SMMHC fusion protein transdominantly inhibits definitive hematopoiesis, but not to the same extent as homozygous loss of Runx1 or Cbfb. CBFbeta-SMMHC preferentially inhibits the differentiation of myeloid lineage cells, while increasing the number of blastlike cells in culture.

Animals↗

PubMed2006

Normal hematopoiesis after conditional targeting of RXRalpha in murine hematopoietic stem/progenitor cells.

Because of the retinoic acid receptor-alpha (RARalpha) gene's involvement in acute promyelocytic leukemia, the important role of RARs in hematopoiesis is now well established. However, relatively few studies of hematopoiesis have focused on the role of the retinoid X receptors (RXRs), the obligate heterodimeric partners of the RARs. We sought to establish whether conditional targeting of RXRalpha in early hematopoietic progenitors, ideally to the level of the hematopoietic stem cell (HSC), would compromise hematopoiesis. For hematopoietic targeting of RXRalpha, we characterized IFN-inducible MxCre mice for use in studying the role of RXRalpha in hematopoiesis. We established that MxCre executes recombination of loxP-flanked RXRalpha in hematopoietic progenitors immunophenotypically enriched for HSC, leading to widespread and sustained targeting of RXRalpha in hematopoietic cells. However, we found no evidence of hematologic compromise in mice lacking RXRalpha, suggesting that RXRalpha is dispensable for normal murine hematopoiesis. Nonetheless, RXRalpha null bone marrow cells cultured in methylcellulose form colonies more efficiently than bone marrow cells obtained from control mice. This result suggests that although RXRalpha is not required for murine hematopoiesis, there may be hematopoietic signaling pathways that respond selectively to RXRalpha or settings in which combined expression of RXR (alpha, beta, and gamma) is limiting.

Animals↗

PubMed1998

Is hematopoiesis under the influence of neural and neuroendocrine mechanisms?

It is well recognized that the immune response is under the influence of a variety of neural or neuroendocrine mechanisms. Much less studied is the possible influence of these mechanisms on hematopoiesis. Here I review the existing evidence about a neural and/or neuroendocrine regulation of hematopoiesis. The physiology of the blood forming system seems to be controlled at three levels, i.e. at the cellular level by the bone marrow stroma, at the humoral level by hematopoietic cytokines and finally by catecholamines and neuroendocrine factors. Bone marrow catecholamines originate from sympathetic nerve fibers and from hematopoietic cells directly. Catecholamines of neural origin show a circadian rhythmicity. Adrenoceptors present on bone marrow cells include the alpha 1-subtype which seems to mediate the catecholaminergic control of hematopoiesis. Neuroendocrine factors including substance P, neurokinin-A and the pineal hormone melatonin might also influence hematopoiesis by affecting hematopoietic cytokines. In particular, melatonin seems to affect hematopoiesis via the induction in bone marrow T-helper cells of two novel opioid cytokines. A complete understanding of the neural and neuroendocrine regulation of hematopoiesis might provide new conceptual and therapeutic perspectives in a variety of hematopoietic and immune diseases.

Animals↗

PubMed2000

Histometrical and three-dimensional analyses of liver hematopoiesis in the mouse embryo.

The development and cytoarchitectures of liver hematopoiesis in the mouse from 10 to 19 days of gestation were examined by light and electron microscopy. In fetal liver hematopoiesis, four stages were identified: Stage I, the onset of hematopoiesis at 10 days; Stage II, expansion of the volume of the hematopoietic compartment at 11 and 12 days; Stage III, the peak in the volume of the hematopoietic compartment at 13 and 14 days; and Stage IV, the involution of hematopoiesis after 15 days. During Stages I-II, hematopoietic stem cells appeared to move from the sinusoidal lumina into primitive hepatic cell cords through the sinusoidal endothelium to give rise to colonies among hepatoblasts. At Stage III, the hematopoietic colonies formed ellipsoidal foci as a structural unit of hematopoiesis. These foci were 35-70 x 20-40 microm in size, and erythroblastic islands could be observed in the center of each. Each island contained central macrophages surrounded by a ring of erythroblasts. The macrophages underwent mitosis, showing close contact with the erythroblasts, after which the hematopoietic foci appeared as cords. At Stage IV, these cord-shaped hematopoietic foci became disrupted, and round solitary foci including macrophages appeared within the hepatic cell cords on meandering sinusoids. In fetal liver hematopoiesis, macrophages could be one of the major cell components comprising the hematopoietic microenvironment, especially at Stages II and III.

Animals↗

PubMed1999

[Biological properties of reconstructed mouse hematopoiesis with hematopoietic stem cells transfected by bcl-2 gene].

OBJECTIVE: To observe resistance to radiochemical agents in the mice reconstructed hematopoiesis with hematopoietic stem cells transfected by bcl-2 gene. METHODS: The plasmid containing bcl-2 cDNA retrovirus vector was transfected to PA317 cells with Lipofecaine kite. A PA317 cell clone(D3) with high virus titer was obtained through G418 selection. The virus supernatant of D3 clone cells was used to transfect mouse embryo-liver hematopoietic stem cells. Hematopoiesis in the mice treated with lethal dose irradiation was reconstructed by hematopoietic stem cells transfected with bcl-2 gene. The resistance to radiochemical agents in the mice with reconstructed hematopoiesis was evaluated according to the number of WBC of periphereal blood and mononuclear cells of bone marrow, CFU-S and CFU-S regeneration. RESULTS: The expression of bcl-2 protein was increased in the hematopoietic cells transfected by bcl-2 gene. The mice reconstructed hematopoiesis by stem cells transfected bcl-2 gene can tolerate high dose combined with chemotherapy and radiation of middle dose. The mice reconstructed hematopoiesis with stem cells transfected bcl-2 gene survived over one year, no tumors were found. CONCLUSION: The mice with reconstructed hematopoiesis by stem cells carried bcl-2 gene possess the ability of resistance to radiochemical agents, even only part of hematopoietic stem cells were transfected with bcl-2 gene.

Animals↗

PubMed1991

Clonal hematopoiesis in patients with acquired aplastic anemia.

To determine whether patients with acquired asplastic anemia (AA) exhibit clonal hematopoiesis, we used restriction fragment length polymorphisms of the X-linked genes phosphoglycerate kinase (PGK1) and hypoxanthine phosphoribosyltransferase (HPRT) and the X-linked probe M27 beta. Of the 19 female patients studied, 18 (95%) patients were informative for at least one marker. Of these, eight patients (42%) were heterozygous for PGK1, two (11%) for HPRT, and 16 (84%) for M27 beta. In 13 (72%) patients, a monoclonal pattern was found. Analysis of purified cell suspensions of four of these patients showed that both myeloid and lymphoid cells were of monoclonal origin, indicating the involvement of an early stem cell. The four patients who were studied at presentation all showed a monoclonal pattern. One of these patients showed a spontaneous recovery despite persistent clonal hematopoiesis. The presence of either clonal or polyclonal hematopoiesis did not show a correlation with the response to antithymocyte globulin (ATG) treatment. A relapse after ATG was also seen in a patient exhibiting polyclonal hematopoiesis. Conversely, a monoclonal pattern did not preclude the occurrence of a partial or complete response to ATG. Other potential markers to study clonality, including cytogenetic abnormalities or point mutations of the N-ras protooncogene, were not found in any of the patients. It is concluded that patients with AA may exhibit clonal hematopoiesis. The significance with respect to evolution to disorders with clonal hematopoiesis like paroxysmal nocturnal hemoglobinuria, myelodysplasia, and acute leukemia remains to be determined.

Adolescent↗

PubMed2004

Hematopoiesis is severely altered in mice with an induced osteoblast deficiency.

We previously reported a transgenic mouse model expressing herpesvirus thymidine kinase (TK) gene under the control of a 2.3-kilobase fragment of the rat collagen alpha1 type I promoter (Col2.3 Delta TK). This construct confers lineage-specific expression in developing osteoblasts, allowing the conditional ablation of osteoblast lineage after treatment with ganciclovir (GCV). After GCV treatment these mice have profound alterations on bone formation leading to a progressive bone loss. In addition, treated animals also lose bone marrow cellularity. In this report we characterized hematopoietic parameters in GCV-treated Col2.3 Delta TK mice, and we show that after treatment transgenic animals lose lymphoid, erythroid, and myeloid progenitors in the bone marrow, followed by decreases in the number of hematopoietic stem cells (HSCs). Together with the decrease in bone marrow hematopoiesis, active extramedullary hematopoiesis was observed in the spleen and liver, as measured by an increase in peripheral HSCs and active primary in vitro hematopoiesis. After withdrawal of GCV, osteoblasts reappeared in the bone compartment together with a recovery of medullary and decrease in extramedullary hematopoiesis. These observations directly demonstrate the role of osteoblasts in hematopoiesis and provide a model to study the interactions between the mesenchymal and hematopoietic compartments in the marrow.

Animals↗