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The effects of a single non-carcinogenic dose of 15 mg/kg methylnitrosourea (MNU) on the immune and hematopoietic systems of adult specific-pathogen-free (SPF) cats were determined. The cell-mediated-immune (CMI) system was markedly suppressed, as evidenced by: (i) Prolonged cutaneous allograft retention time (41-84 days); (ii) Decreased lymphocyte blast transformation response to mitogens (2% of pretreatment response to pokeweed mitogen or concanavalin A) and antigen (12% of untreated control cat response to keyhole limpet hemocyanin); (iii) Reduced number of absolute erythrocyte-rosetting T-cells in the peripheral blood. This immunosuppression lasted at least 3 months, the duration of the experiment. Suppression of the hematopoietic system was also noted as evidenced by: (i) Peripheral lymphopenia lasting 3 months and neutropenia lasting 3 weeks; (ii) Bone marrow hypocellularity lasting 3 weeks; (iii) Hypoplasia of neutrophilic precursors lasting 3 weeks and erythroid precursors lasting 4 days. It was concluded that a single non-carcinogenic dose of MNU induces a prolonged suppression of the CMI system and a brief suppression of hematopoiesis in adult SPF cats. The immunosuppression may in part be responsible for the previously observed increased susceptibility to feline leukemia virus infection and disease of adult SPF cats treated with MNU.
Hematopoietic stem cell gene therapy is potentially curative for a number of inherited and acquired disorders. However, poor gene transfer and expression in repopulating hematopoietic stem cells attenuate this potential. Here we review potential means of conferring a selective advantage to hematopoietic stem cells and their progeny, and discuss the issues that surround the use of selective advantages in vivo.
The mouse hematopoietic system was subjected to repeated depletion and regeneration either by serial transfer of bone marrow cells through lethally irradiated recipients or by repeated treatment with the cycle-active drug hydroxyurea (HU). The capacity of surviving stem cells to proliferate and self-renew was assayed at intervals by two methods: (a) the spleen colony method; and (b) competitive repopulation of irradiated recipients using chromosome markers, with normal bone marrow cells as an internal control. The progressive decline in stem cell function that occurred during serial transfer of bone marrow and that had already begun after a single transfer was not seen during HU treatment; up to 25 pairs of HU injections given over more than 1 yr had no discernible effect on the number of stem cells present 3 wk after the final injection or on their capacity to self-renew. Within 2 d after exposure to HU, the average self-renewal capacity of surviving stem cells was enhanced. This implies that the drug selectively eliminates poorly self-renewing stem cells and hence that these enter cycle more readily than stem cells with a high self-replicative potential. However, the fact of being in cycle at the time of injection did not of itself affect self-renewal. The results show that serial transfer of bone marrow is not a valid method for studying clonal aging phenomena because it does not fulfill the assumptions on which such studies are based. No evidence was obtained for any intrinsic limitation in the capacity of bone marrow populations for repeated regeneration after HU-induced depletion. However, this does not necessarily imply that individual hematopoietic clones are capable of indefinite expansion because hematopoiesis may (as suggested by the relative resistance of highly self-replicative stem cells to mitogenic signals) proceed on the basis of clonal succession.
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Alcohol has a variety of pathologic effects on hematopoiesis. It directly damages erythroid precursors, thereby contributing to macrocytosis and the anemic state of chronic alcoholics. Megaloblastic anemia in chronic alcoholism results from a combination of nutritional deficiency and the effect of ethanol as a folate antagonist. Experimental studies suggest that alcohol may disturb hepatic folate metabolism. Ethanol induces sideroblastic anemia, perhaps by direct interference with heme synthesis. Further, chronic ingestion of alcohol can lead to various types of hemolytic anemia caused by alterations in the erythrocyte membrane lipids which occur in association with alcoholic liver disease. Alcohol directly suppresses platelet formation and decreases the platelet life span. These two mechanisms contribute to thrombocytopenia which is a common complication to chronic alcoholism. Since ethanol also interferes with platelet function, prolongation of bleeding the time is common at all stages of alcoholism. Chronic ingestion of alcohol is associated with a diminished marrow granulocyte reserve and may lead to neutrocytopenia. Ethanol-induced dysfunction of granulocytes, monocyte-macrophages and T-lymphocytes undoubtedly contributes to the predisposition to infection observed in alcoholics. In contrast to alcohol-induced changes in liver, heart and central nervous system, hematopoietic disorders are reversible after alcohol withdrawal.
OBJECTIVE: Hematopoietic stem cells (HSCs) and colony-forming progenitor cells (CFCs) are believed to migrate from liver to bone marrow (BM) around the time of birth, where they remain throughout the animal's life. Although in mice the spleen is also a hematopoietic organ, neither the origin nor the contribution of spleen HSCs to hematopoietic homeostasis has been assessed relative to that of BM HSCs. To investigate these issues we quantitated CFC and HSC activity in the spleen, BM, peripheral blood, and liver of the mouse during ontogeny. METHODS: CFCs were assessed by clonogenic colony formation, and HSCs by long-term reconstituting ability. RESULTS: CFCs gradually increased in the BM and decreased in the liver with age. Increased prevalence of CFCs in fetal and pup blood occurred at day (d) 12 postcoitus (pc) and during the period of d16 pc to 4d postbirth, corresponding to the times when hematopoietic cells migrate from the yolk sac and/or aorta-gonad-mesonephros (AGM) to the fetal liver and from the neonatal liver to the BM, respectively. In the spleen, CFCs displayed two peaks of activity at 2d and 14d-15d postbirth. Spleen HSCs also fluctuated during this time period. Neonatal splenectomy did not alter CFC or HSC frequencies in the BM, but CFCs increased in the livers of splenectomized mice. CONCLUSIONS: These data demonstrate that the liver may act as a site of extramedullary hematopoiesis in the neonate, especially in the absence of the spleen, and imply that the spleen, BM, and liver cooperatively contribute to hematopoietic homeostasis.
A new transgenic mouse has been generated in which the proto-oncogene BCL-2 is ubiquitously overexpressed. H2K-BCL-2 transgenic mice overexpress BCL-2 in all cells of the hematolymphoid system and have been used to assess the role of BCL-2 in protecting cells of the hematolymphoid system from the consequences of ionizing radiation. We have expanded on previous studies that have demonstrated protection for specific (lymphoid) cell populations and show that systemic overexpression of BCL-2 can protect the hematopoietic system as a whole, including hematopoietic stem cells (HSC), thus increasing the radioresistance of the animal. The increase in radioresistance in H2K-BCL-2 transgenic mice has two components: an increase in the radioresistance of individual cells and, to a lesser extent, an increase in the size of certain critically important cell populations, such as HSC. Bone marrow transplantation experiments show that the increased radioresistance of the transgenic animals is provided by cells of the hematopoietic system. Protection against the consequences of irradiation is not limited to the increased expression levels of BCL-2 in transgenic mice; levels of endogenous BCL-2 are higher in lymphocyte populations that survive irradiation in wild-type mice. We show that ubiquitous overexpression of BCL-2 in the hematopoietic system can be used to increase the resistance of animals to lethal challenges such as irradiation.
Despite improvements in retrovirus-mediated gene transfer to primitive murine hematopoietic cells, high-level reconstitution with provirally marked cells with continued expression of the transferred gene(s) remains a challenge in many situations. We evaluated a physical preselection strategy for isolating transduced cells after their infection with different vectors. The small (240-bp) cDNA coding region for the human CD24 cell-surface antigen was inserted into myeloproliferative sarcoma virus (MPSV) and murine stem cell virus (MSCV)-based retroviral vectors such that expression of CD24 was under the control of the viral long terminal repeat (LTR). After infection of (Ly-5.1) mouse bone marrow (BM), those expressing CD24 were isolated by fluorescence-activated cell sorting (FACS) and a transplant dose estimated to contain approximately 12 +/- 4 long-term competitive repopulating cells (CRU) injected into lethally irradiated congenic Ly-5.2 recipients. Six months later, virtually all recipients showed high-level (> 80%) reconstitution of their BM and thymus with Ly-5.1 (transplant-derived) cells, the majority of which were also transduced (mean of 2.5 or 2.6 proviral copies for the two vectors). All spleen colonies generated in secondary recipients of cells obtained from the BM of the 6-month-old primary mice contained the provirus. However, only in recipients of MSCVCD24-infected marrow was a correspondingly high level of CD24 expression seen: a maximum of 88% for whole BM (all mice positive), 58% for peripheral blood leukocytes (all mice positive), and 21% for thymocytes (11 of 13 mice positive). CD24 was also readily detected on the regenerated Sca-1+Lin- cells present in the primary and secondary recipients when these were studied 6 months post-transplant, but again on more of the Sca-1+Lin- cells in recipients of MSCVCD24-infected cells as compared to recipients of MPSVCD24-infected cells. These results point to the utility of preselection strategies and suggest an approach for the development of better vectors for achieving regulated, lineage-specific or stage-specific gene expression patterns in particular subsets of hematopoietic cells.
BACKGROUND: Circulating hematopoietic peripheral blood progenitor cells (PBPCs) may contribute to the regeneration of nonhematopoietic organs. An increase in circulating PBPC numbers may enhance this process. Therefore, an exploratory trial of repeated PBPC mobilization in patients with chronic heart failure was conducted. The safety and cardiovascular efficacy data have been described elsewhere. In the hematopoietic system, the trial offered an opportunity to study several new aspects of granulocyte-colony-stimulating factor (G-CSF) action. STUDY DESIGN AND METHODS: Fourteen male patients with chronic heart failure were treated successively with G-CSF (four 10-day treatment periods interrupted by treatment-free intervals of equal length; daily dose adjustment to maintain a white blood cell [WBC] count of 45 x 10(9)-50 x 10(9)/L). RESULTS: G-CSF induced a rapid increase in cells of all WBC lineages with return to levels equal to (neutrophilic, eosinophilic, and basophilic granulocytes) or lower than those before treatment (monocytes, lymphocytes) during the treatment-free intervals. Red cell counts remained unchanged, but platelet counts decreased followed by rebound thrombocytosis. The extent of CD34+ cell mobilization was highly variable. For each patient, the changes induced were identical through all cycles, but the G-CSF dose required in the first cycle was significantly higher than in subsequent cycles. In the cohort of patients, an inverse correlation was observed between the WBC level reached and the dose of G-CSF administered. CONCLUSIONS: Rapid alternation between PBPC mobilization and recovery periods is feasible, with identical alterations in all treatment cycles. G-CSF responsiveness varies among patients and is increased by pretreatment with G-CSF.
To investigate the relationship of the hematopoietic system to the loss of bone due to ovarian hormone deficiency, we examined the effects of ovariectomy and estrogen administration on the thymus, spleen and the bone marrow, and on the proliferation of marrow progenitors of osteoclasts. We also assessed the effects of daily administration of interleukin-1 receptor antagonist (IL-1ra) on bone loss due to ovarian hormone deficiency. Ovariectomy resulted in decreased cancellous bone volume, increased trabecular osteoblast and osteoclast numbers, and increased serum alkaline phosphatase levels that were prevented by 17 beta-estradiol treatment. Thymus weight, spleen weight, thymus and spleen lymphocytes, and bone marrow monocytes and lymphocytes also increased significantly following ovariectomy, and the increases were suppressed by 17 beta-estradiol. Ovariectomy, in addition, caused a 4-fold increase in the number of tartrate resistant acid phosphatase (TRAP)-positive multinucleated cells formed in cultures of marrow cells and the increase was partially inhibited by 17 beta-estradiol. IL-1ra administration did not prevent the bone loss due to ovariectomy. Our findings indicate that ovariectomy-induced bone loss in the rat is accompanied by marked changes in the hematopoietic system, and that these changes are modulated by estrogen administration. In spite of the negative finding with IL-1ra, the nature of the involvement of the hematopoietic system in the pathogenesis of bone loss due to ovarian hormone deficiency merits continued exploration.
Physiological, experimental and theoretical aspects concerning haemopoietic inhibitors are reviewed. In the paper there are also discussed future research directions of this branch of haematology.
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Thirteen cell lines of the human hematopoietic system were tested for expression of calpastatin at three different levels (mRNA, product and activity). The amount of calpastatin product and its inhibitory activity varied markedly depending upon cell types or human T-cell leukemia virus type I infection, although there were difference in the expression at the transcriptional level. Cell lines with high content of calpastatin comprised T-cell lineage infected by human T-cell leukemia virus type I, B-cell line and myelocytic leukemia cell lines. Non-infected T-cell lines and null cell line revealed themselves as poor in both calpastatin products and inhibitor activities. Two different molecular forms of calpastatin were observed: a 102-kDa form in T- and B-cell lines and a 94-kDa form in one of myelocytic cells. Three mRNA species of calpastatin (3.8, 3.0 and 2.5 kb) were identified in human hematopoietic system cells.
OBJECTIVE: To study the hormesis effect on hematopoietic system induced by low dose radiation. METHOD: CFU-GM and BFU-E were cultured in methylcellulose semi-solid culture system, levels of GM-CSF and IL-3 were assayed by ELISA and mRNA levels of GM-CSF, G-CSF, IL-3 by in situ hybridization, narrow line hybridization and Northern blot. RESULTS: (1) The in vitro yields of CFU-GM and BFU-E from radiated mice was higher than that from the control. (2) The serum protein level of GM-CSF increased obviously than that of controls; (3) mRNA levels of GM-CSF and G-CSF were also increased. CONCLUSION: There is hormesis effect on hematopoietic system induced by low dose radiation, which may be related to the increasing of cytokines.
The identity of the cells giving rise to the hematopoietic system in the mouse embryo are unknown. The results presented here strongly suggest that hematopoietic cells are derived from a nonhematopoietic cell population that has been previously thought to give rise to the germ cells. These cells are called primordial germ cells (PGCs) and can be recognized as large cells showing blebbing and pseudopodial extrusions on their surface. They are alkaline phosphatase (AP) positive and possess a stage-specific embryonic antigen (SSEA-1) on their surface. They represent a small pool of cells in the extraembryonic mesoderm at the base of the allantois in late day-6 embryos. Primordial germ cells from 7.5- and 8.5-day visceral yolk sac and embryo proper form AP+ and SSEA-1+ colonies within 5 days when grown on an embryonic fibroblast feeder cell layer in the presence of leukemia inhibitory factor (LIF), stem cell factor (SCF), and interleukin-3 (IL-3). Individual colonies taken from day-5 cultures can be shown to differentiate into erythroid lineage cells in secondary methyl cellulose culture and produce secondary and tertiary PGCs in the presence of LIF, SCF, and IL-3. Cells taken from the region of the allantois and primitive streak can form colonies on hydrophilic Teflon (DuPont, Wilmington, DE) foils precoated with collagen and fibronectin. The cells from these colonies were then shown to form cobblestone areas on irradiated adult bone marrow stromal layers, indicating that the most primitive in vitro hematopoietic stem cell, the cobblestone-area forming cell (CAFC), was present. PGC colonies were grown in methyl cellulose in the presence of LIF, SCF, and IL-3 for 5 days, and the colonies were removed and passaged 3 times on pretreated extracellular matrix hydrophilic Teflon foils. After each passage, the cells were assayed for their differentiation capacity and PGC content. After the last passage, the number of CAFCs was also determined. It was found that, under these conditions, the PGC population expanded more than 400-fold and also contained CAFCs. It is postulated that the PGC represents a totipotent stem cell population capable of producing a variety of different cell types including cells of the hematopoietic system.
Current knowledge of the immune and hematopoietic systems is reviewed. All blood cells are derived from the totipotent stem cell, also known as the pluripotent stem cell. The differentiation of pluripotent peripheral stem cells into blood cells is controlled by a variety of biologic response modifiers, including colony-stimulating factors (CSFs) and interleukins. Among the known CSFs are stem cell growth factor, granulocyte-macrophage CSF, multilineage CSF (interleukin-3), granulocyte CSF, macrophage CSF, and erythropoietin. CSFs are categorized as class I (those that stimulate the production of several types of blood cells; also called pluripotent) and class II (those that stimulate only one cell line; also called unipotent). Effects of CSFs can be studied using laboratory tests of colony-forming-unit activity. Pathogens entering the body through damaged skin or mucous membranes are met with both a cellular response (neutrophils, macrophages, cytotoxic T lymphocytes, and natural killer cells) and a humoral response (antibodies and complement). There is interplay between these two arms of the immune system to defend against foreign antigens. This interplay can occur by cell-to-cell contact and by cytokines. Hematopoietic and immune cells of the body are produced and destroyed under precise control of many different biologic response modifiers, including the colony-stimulating factors, interleukins, and interferons.