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Biomedical subjects

G Brecher

Publications and source records attributed to G Brecher.

At least 19 recordsLinked to original sources
PubMed1991

Short- and long-term repopulation of lethally irradiated mice by bone marrow stem cells enriched on the basis of light scatter and Hoechst 33342 fluorescence.

Murine bone marrow subpopulations enriched in hemopoietic stem cells were transfused into lethally irradiated hosts to determine the contribution of host cells and two types of donor cells to marrow repopulation. Donor cell suspensions were a mixture of marrows from two congenic lines of mice containing electrophoretically distinguishable alloenzymes of phosphoglycerate kinase (PGK-A and PGK-B). The donor cells were sorted by high forward light scatter, low-to-intermediate perpendicular light scatter, and low Hoechst 33342 fluorescence intensity. The congenic hosts contained a third distinct marker, glucose phosphate isomerase (GPI-A). The two markers in the donor cells allowed determination of the clones generated by the seeded cells over a 36-week period of observation. The clone number declined rapidly during the first 12 weeks following transplantation and reached stable levels at 20 weeks, indicating the number of long-term repopulating cells (LTRC). The sorted subpopulation was enriched 170-fold for day-13 spleen colony-forming units (CFU-S), 235-fold for cells providing a 30-day survival, and 136- to 160-fold for LTRC. Survival for the 36-week observation period was 40%-100% for groups of hosts receiving 100-3000 sorted cells and 80% for controls receiving 2 x 10(5) unsorted cells. In all groups, similar distribution of phenotypes among peripheral blood erythrocytes, platelets, and lymphocytes at 36 weeks suggested that the repopulating donor stem cells were pluripotential. Transfusion of 3000 sorted cells, containing about 5 LTRC and 60 CFU-S, assured continuous repopulation with 95%-100% donor cells 4 to 36 weeks after transplantation, whereas significant numbers of host cells re-emerged temporarily or permanently when lower numbers of LTRC and CFU-S were transfused. The data indicate that both the quality and quantity of pluripotential stem cells in sorted bone marrow are important for complete long-term marrow reconstitution.

Animals↗
PubMed1988

Pluripotent stem cells with normal or reduced self renewal survive lethal irradiation.

Transfusion with 10,000 or 20,000 marrow cells resulted in 30+ days survival of 15%-50% of mice exposed to an Ld90 or LD100 or radiation. The use of congenic mice with alloenzyme markers permitted the identification of host and donor cells in the peripheral blood of transfused animals. Donor cells were present initially in all hosts. Between 55% and 92% of the animals became 100% host type by 12-24 weeks after transfusion in three separate experiments. To explore whether the temporary repopulation by donor cells was due to short-lived stem cells, the marrows of several primary hosts were transfused into secondary, lethally irradiated hosts. Some of the retransplanted primary donor and host cells persisted only temporarily. It is suggested that some of the donor stem cells in both the primary and secondary hosts had an intrinsically shortened life span.

Animals↗
PubMed1986

Renewal and release of hemopoietic stem cells: does clonal succession exist?

The term "clonal succession" was proposed 20 years ago by Kay to characterize the release of stem cells from their primary pool, followed by the expansion of each cell to a clone and the succession of new clones as the mature cells of each clone are lost because of their finite life span. The authors point out that the events described by Kay as clonal succession are necessary features of hemopoietic proliferation. Clonal succession is equivalent to the universally recognized existence of a self-replicating primary stem cell pool that continuously supplies cells for amplification and maturation to subsequent compartments. The authors object to the term "clonal succession" because it has been used by a number of investigators to characterize specific schemes rather than the general aspects of hemopoietic proliferation, thus leading to confusion. They suggest that the descriptive term, "continuous release of stem cells for differentiation," would be preferable to the use or misuse of "clonal succession."

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PubMed1985

Enhanced proliferation of transfused marrow and reversal of normal growth inhibition of female marrow in male hosts 2 months after sublethal irradiation.

We have previously shown that bone marrow will seed and proliferate in normal recipients. Transfusion of 50 million cells on each of 4 or 5 consecutive days, a total of 200-250 million cells, resulted in the recipient's marrow being 20-40% of donor origin. The present paper reported on the marked enhancement of proliferation of donor cells in animals that were exposed to sublethal doses of irradiation of 300-900 R. Two months later, when their peripheral blood values had returned to normal, they were transfused with 100 million cells. The number of donor cells in the recipients exposed to 600-900 R reached 55-100% at various intervals after transfusion, with controls averaging 24% and never exceeding 40%. Since the transfused cells numbered less than 40% of the host's own complement of marrow cells, they could not replace 100% of them unless they proliferated more rapidly than the host cells. The implied competitive advantage of the donor cells was ascribed to a reduced capacity for self-renewal of the host's irradiated cells. In recipients exposed to 300 R and in nonirradiated controls, female cells failed to grow in male recipients, while male cells grew as well in female as in male hosts. The inhibition of growth of female cells in the male host was abolished by irradiation with 600 or 900 R, or by the exposure of the female donor cells to anti-Thy-1 serum and complement prior to transfusion. Experiments are under way to test the suggested immunologic nature of the inhibition phenomenon.

Animals↗
PubMed1985

Marrow transfusions increase pluripotential stem cells in normal hosts.

In earlier investigations of marrow transfusions into isogeneic, nonirradiated mice, the percentage of donor cells in the recipients' marrow and peripheral blood was found to vary between 16% and 40% following transfusion of 200 million marrow cells. The present experiments demonstrated that the hosts' pluripotential stem cells were elevated to an average of 132% of simultaneously assayed nontransfused controls. The elevation persisted for two months and then returned to normal. The similar magnitude of elevation of pluripotential stem cells and of the percentage of donor cells in the recipients indicates that the seeded stem cells did not replace the hosts' own, but were added to the existing complement of pluripotential cells. Implications for the regulation of stem cell numbers are discussed.

Animals↗
PubMed1985

Role of T cells in sex differences in syngeneic bone marrow transfers.

Transferred marrow cells will proliferate in normal mice not exposed to irradiation or any other type of stem cell depletion when five consecutive transfers of 40 million cells are given. Approximately 25% of the mitotic cells are of male donor origin observed cytogenetically in all of the female recipient spleens and marrow analyzed from two weeks to one and one-half years after transfusions. Male donor stem cells are accepted and form a stable component of the self-renewing stem cell pool. In contrast, only 5% female cells are found in male recipients. This sex difference in engraftment is not hormonal since castration of recipients does not alter the percentage of donor cells. Rigorous T depletion of female donor bone marrow, however, increases the percentage of donor engraftment to the level observed when male marrow, either whole or T depleted, is transferred to female recipients. The success of T-depleted female stem cells to seed male recipients is observed in both C57BL/6, a responder strain in which females readily respond to the H-Y antigen as manifest by skin graft rejection, and CBA/J, a strain in which females do not readily respond to H-Y. In addition, recipient nude BALB/c males, which lack a thymus, fail to accept whole bone marrow from BALB/c females. However, male bone marrow cells seed BALB/c nude females. These studies demonstrate that the poor engraftment of female cells in transfused male recipients is abrogated by the removal of T cells from the donor female marrow.

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PubMed1979

Transplantation of murine bone marrow without prior host irradiation.

The experiments presented test the hypothesis that pluripotential stem cells (assayed in the mouse as CFU-S) are normally not in cycle and that the failure of normal marrow transfusions to take in normal recipients is due to the absence of a stimulus to turn CFU-S into cycle. Following marrow transfusion from male donors into female isogeneic recipients, spleen, liver, and various parts of the skeleton were shielded to protect transfused donor cells from lethal doses of radiation gives to the rest of the body. Percentages of hemopoietic donor and host cells were subsequently determined by karyotyping C banded marrow and spleen metaphases and identifying of Y chromosome. The results support the notion that the failure of normal marrow to take in normal recipients is not due to inadequate numbers of transfused cells. Permanent colonization by donor cells, however, requires not only triggering CFU-S into cycle, but also emptying of 'niches' normally occupied by endogenous CFU-S. Partial body radiation meets both requirements. In addition, the results indicate that recently arrived donor cells, protected in the shielded portion of the body, seed more readily into the irradiated areas of the skeleton than do similarly protected host cells.

Animals↗
PubMed1979

Suppressive effects of chlorphenesin on lymphocyte function in mice and humans.

The immunosuppressive action of chlorphenesin was investigated in a wide variety of in vitro assays for cellular immunity in humans and mice. Chlorphenesin, at doses of 20-50 micrograms/ml, inhibited mitogenic responses of both mouse and human B and T cells. These doses did not kill cells exposed to the drug for 72 hr. Mixed lymphocyte reactions in inbred strains of mice and in unrelated humans were also inhibited at concentrations of about 50 micrograms/ml. However, the generation of cytotoxic T cells in cell-mediated lympholysis assays was not inhibited to the same degree as proliferation in mixed lymphocyte reaction and the cytotoxic potential of presensitized mouse T cells for allogeneic targets was totally unaffected. These studies suggest that chlorphenesin may have a broad spectrum of suppressive effects both on T and B cells and that the predominant inhibition of proliferative responses in these cells may reduce the expansion of clones of immunocompetent cells in vivo.

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PubMed1977

Clinical laboratory use in the evaluation of anemia.

Follow-up tests ordered on 258 consecutively examined inpatients with low hemoglobin values on admission were analyzed. The appropriateness of the follow-up tests was evaluated by chart review after preselection by an algorithm. When the cause of the anemia was known or was irrelevant in view of the patient's clinical status, the laboratory use was judged to be adequate. Seventy-one percent of patients studied had an adequate follow-up, though 11% had nonindicated tests performed, scored as laboratory overuse. Twenty-four percent had no follow-up, scored as laboratory underuse. Five percent did not have all indicated tests done and had nonindicated tests done, scored as a mixture of underuse and overuse. Potential remedies to correct misuse are discussed.

Anemia↗
PubMed1977

Pluripotential and committed hemopoietic stem cells. A hypothesis.

The hypothesis is proposed that regulation of hemopoiesis is largely accomplished by expansion or contraction of the committed stem cell compartments and that pluripotential stem cells are normally not involved or in cycle. The thesis appears supported by the fact that erythropoietin affects the committed red cell precursors, that 98% of marrow mitoses have been shown to occur in cells clearly recognizable as red or white cell precursors (while the pluripotential stem cells by definition are not so recognizable), and that it has been shown (by the spleen nodule assay) that the pluripotential stem cell compartment in the marrow cannot be readily expanded. The major objection to the proposed hypothesis are tritiated thymidine suicide data, which suggest that up to 20% of pluripotential stem cells may be constantly in cycle in some stains of mice. Preliminary experimental evidence supporting the hypothesis has been obtained: normal pluripotential stem cells which transfused into normal isologous mice are not lost as has been assumed but proliferate after irradiation, suggesting that it takes a special stimulus to "turn-on" the normally quiescent pluripotential stem cells.

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