Biomedical subjects

Gerald G Wulf

Publications and source records attributed to Gerald G Wulf.

9 recordsLinked to original sources

PubMed2006

[Mesenchymal stem cells from bone marrow. Phenotype, aspects of biology, and clinical perspectives].

BACKGROUND: Since their initial description by Friedenstein et al. 30 years ago, mesenchymal stem cells have been characterized as a cell population of the bone marrow, which is easily accessible and readily manageable for in vitro manipulation. RESULTS: Cell biology studies have delineated the phenotype of mesenchymal stem cells, optimized the conditions for in vitro expansion, and documented their differentiation capacity along mesodermal lineages. First clinical applications as an adjunct to stem cell transplantation regimens have shown some potential in osteogenic regeneration as well as immunosuppressive effects after allogeneic stem cell transplantation. Animal studies have further shown, that mesenchymal stem cells may serve as vehicles for the transfer of genetic material. Preclinical studies remain, however, to answer numerous questions with regard to populational heterogeneity and the physiological roles of this cell compartment. CONCLUSION: Further preclinical studies as well as clinical cell therapy studies are essential to fully exploit the potential of mesenchymal stem cells in regenerative medicine, cellular immunotherapy, and gene therapy.

Animals↗

PubMed2006

CD45 monoclonal antibody-mediated cytolysis of human NK and T lymphoma cells.

BACKGROUND AND OBJECTIVES: The CD45 rat monoclonal IgG2b antibodies YTH24.5 and YTH54.12 act synergistically to produce cytolysis of normal lymphocytes and have been safely given to patients in conditioning regimens for allogeneic stem cell transplantation. The antibodies are not lytic for hematopoietic stem cells, but the depletion of the lymphoid lineage cells is profound and sustained. DESIGN AND METHODS: We evaluated the YTH24.5 and YTH54.12 pair for complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and apoptotic and antiproliferative effects against a panel of non-Hodgkin's lymphoma (NHL) cell lines and against primary specimens. RESULTS: Significant CDC activity was observed against two of two NK and one of four T lymphoma cell lines; moderate activity was seen against two of four T, and four of eight B lymphoma cell lines. In the responding cell lines, the lytic activity of YTH24.5 and YTH54.12 was as least as strong as that of alemtuzumab or antithymocyte globulin. The combination of YTH24.5 and YTH54.12 also induced ADCC in one of two NK and two of four T lymphoma cell lines, as well as three primary specimens, but was ineffective in B-NHL. The antibodies decreased viability in two of two NK and one lymphoma cell line, measurable as apoptosis or direct cell death in the cell lines NK92 and CEM, respectively. In a tumor model of Jurkat lymphoma in SCID mice, administration of YTH24.5 and YTH54.12 impaired local tumor growth and delayed systemic disease progression. INTERPRETATION AND CONCLUSIONS: CD45 antibodies YTH24.5 and YTH54.12 have lytic activity against NK and T lymphoma cells via CDC and ADCC, are effective in a preclinical tumor model, and may be candidates for immunotherapeutic approaches to the treatment of human NK and T cell lymphoma.

Adolescent↗

PubMed2004

An in vivo propagated human acute myeloid leukemia expressing ABCA3.

Analyzing the regenerative compartment in the blast cell population of patients with acute myeloid leukemia (AML) may yield important insights into the mechanisms of disease progression. Here we present findings with a human AML cell line (AML-SP1), initiated from leukemic precursor cells and consecutively propagated by serial xenotransplantation in vivo. AML-SP1 maintained the characteristics of a human AML, consistently exhibiting a small leukemic side population (SP) of blast cells with high Hoechst 33342 exclusion. In the AML-SP1 line, an increased expression of the ABC transporters MDR1, MRP, ABCG2 and ABCA3 was found in the SP cells. The detection of ABCA3 in leukemic progenitor cells merits further investigation with regard to intracellular drug transport in AML blast cells. In vivo propagation of leukemias, such as AML-SP1 is a model system of maintaining the populational heterogeneity of AML disease, especially the unique characteristics of leukemic SP cells.

ATP-Binding Cassette Transporters↗

PubMed2004

ABC transporter ABCA3 is expressed in acute myeloid leukemia blast cells and participates in vesicular transport.

Drug resistance is a major issue in the treatment of acute myeloid leukemia (AML), and drug efflux by ATP-binding-cassette (ABC) transporters is one of the main mechanism involved in this resistance. We determined the prevalence of the intracellular transporter ABCA3 in specimens from patients with AML, and addressed its biology with attention to intracellular compartmentalization.

ATP-Binding Cassette Transporters↗

PubMed2003

Complement-fixing CD45 monoclonal antibodies to facilitate stem cell transplantation in mouse and man.

Broadening the applicability of stem cell therapies requires safer preparative regimens for patients. The CD45 antigen is present on all cells of the hematopoietic lineage, and using a murine model, we determined whether a lytic CD45 monoclonal antibody could produce persistent aplasia and whether it could facilitate syngeneic or allogeneic stem cell engraftment. After its systemic administration, we found that all leukocyte subsets in peripheral blood were markedly diminished, but only the effect on the lymphoid compartment was sustained and marrow progenitor cells were spared from destruction. Given the transient effects of the monoclonal antibody on myelopoiesis and the more persistent effects on lymphopoiesis, we asked whether this agent could contribute to donor hemopoietic engraftment after subablative transplantation. Treatment with anti-CD45 alone did not enhance syngeneic engraftment, consistent with its inability to destroy progenitor cells and permit competitive repopulation with syngeneic donor stem cells. By contrast, the combination of anti-CD45 and an otherwise inactive dose of total-body irradiation allowed engraftment of H2 fully allogeneic donor stem cells. We attribute this result to the recipient immunosuppression produced by depletion of CD45-positive lymphocytes. We next assessed a pair of unconjugated rat anti-human CD45 monoclonal antibodies (MAbs), YTH54.12 and YTH25.4, in a clinical trial in patients who were to receive stem cell transplantation for acute leukemia. The maximum tolerated dose of these MAbs, 400 microg/kg/day, produced a pattern of response identical to that seen in the mice, with marked reductions in circulating lymphoid and myeloid cells and sparing of early marrow progenitors. In two of three patients with active leukemia, the MAbs also produced a decrease in the percentage of leukemic blast cells in bone marrow. These pre-clinical and clinical results warrant further evaluation of anti-CD45 MAbs in subablative preparative regimens for stem cell transplantation.

Animals↗

PubMed2003

Cells of the hepatic side population contribute to liver regeneration and can be replenished with bone marrow stem cells.

BACKGROUND AND OBJECTIVES: The aim of this study was to determine whether Hoechst effluxing side population cells isolated from murine liver represent hepatic stem cells, and to examine whether hepatic side population cells arise from bone marrow side population cells. DESIGN AND METHODS: Side population cells were isolated from murine liver by flow cytometry after Hoechst staining and injected directly into murine livers of animals pre-treated with the hepatotoxin 3,5 diethoxy carbonyl-1, 4-dihydrocollidine (DDC). Y-chromosome in situ hybridization was used to track donor cells in the livers. In addition, bone marrow side population cells were stably engrafted into the hematopoietic system of sublethally irradiated recipients and CD45 alleleic staining and Y-chromosome in situ hybridization were used to track side population cell progeny in the liver. RESULTS: In vitro, CD45pos and CD45neg hepatic SP cells gave rise to hematopoietic colonies and mixed colonies of hematopoietic and hepatic differentiation. After orthotopic liver cell transplantation, donor hepatic side population cells contributed to the regeneration of mature liver parenchyma and bile duct epithelium. After transplantation of bone marrow side population cells, both CD45pos and CD45neg hepatic side population cells were partially derived from donor stem cells and could be recruited to repair liver damage after treatment with DDC. INTERPRETATION AND CONCLUSIONS: These findings introduce hepatic side population cells as a facultative liver-regenerating population, reveal interchangeability of tissue stem cells at the level of the side population, and suggest that bone marrow-derived side population cells might be exploited for the repair of diseased or damaged liver.

Animals↗

PubMed2002

Anti-CD45-mediated cytoreduction to facilitate allogeneic stem cell transplantation.

The CD45 antigen is present on all cells of the hematopoietic lineage. Using a murine model, we have determined whether a lytic CD45 monoclonal antibody can produce persistent aplasia and whether it could facilitate syngeneic or allogeneic stem cell engraftment. After its systemic administration, we found saturating quantities of the antibody on all cells expressing the CD45 antigen, both in marrow and in lymphoid organs. All leukocyte subsets in peripheral blood were markedly diminished during or soon after anti-CD45 treatment, but only the effect on the lymphoid compartment was sustained. In contrast to the prolonged depletion of T and B lymphocytes from the thymus and spleen, peripheral blood neutrophils began to recover within 24 hours after the first anti-CD45 injection and marrow progenitor cells were spared from destruction, despite being coated with saturating quantities of anti-CD45. Given the transient effects of the monoclonal antibody on myelopoiesis and the more persistent effects on lymphopoiesis, we asked whether this agent could contribute to donor hematopoietic engraftment following nonmyeloablative transplantation. Treatment with anti-CD45 alone did not enhance syngeneic engraftment, consistent with its inability to destroy progenitor cells and permit competitive repopulation with syngeneic donor stem cells. By contrast, the combination of anti-CD45 and an otherwise inactive dose of total-body irradiation allowed engraftment of H2 fully allogeneic donor stem cells. We attribute this result to the recipient immunosuppression produced by depletion of CD45(+) lymphocytes. Monoclonal antibodies of this type may therefore have an adjunctive role in nonmyeloablative conditioning regimens for allogeneic stem cell transplantation.

Animals↗

PubMed2002

Stem cells: a minireview.

The identification of adult-derived stem cells which maintain plasticity throughout the course of a lifetime, has transformed the field of stem cell biology. Bone marrow derived hematopoietic stem cells (HSC) are the most well-characterized population of these multipotential cells. First identified for their ability to reconstitute blood lineages and rescue lethally irradiated hosts, these cells have also been shown to differentiate and integrate into skeletal muscle, cardiac myocytes, vascular endothelium, liver, and brain tissue. Various populations of HSC are being studied, exploiting cell surface marker expression, such as Sca-1, c-kit, CD34, and lin; as well as the abilityto efflux the vital dye Hoecsht 33342. Detection of engrafted donor derived cells into various tissue types in vivo is a laborious process and may involve detection of beta-galactosidase via colorimetric reaction or antibody labeling or green fluorescent protein (GFP) via fluorescence microscopy, as well as in situ hybridization to detect the Y-chromosome. Using these techniques, the search has begun for tissue specific stem cells capable of host tissue regeneration, self renewal, and transdifferentiation. Caution is urged when interpreting these types of experiments because although they are stimulating, limitations of the technologies may provide misleading results.

Animals↗

PubMedDate not supplied

Mesengenic progenitor cells derived from human placenta.

Progenitor cells with differentiation capacity along multiple mesengenic lineages are attractive tools for numerous purposes in regenerative medicine. Such mesengenic progenitor cells have been isolated from adult mammalian bone marrow, and we here report placental tissue as an alternative source for these cells. By means of dissection/proteinase digestion techniques, high numbers of viable mononuclear cells were harvested from human placenta at term, and a mesenchymal cell population with characteristic expression of CD9, CD29, and CD73 was obtained in culture. The in vitro growth behavior of such placenta-derived mesengenic cells was similar to that of human bone marrow mesengenic progenitor cells. After in vitro propagation for more than three passages the cells were exclusively of maternal origin. Differentiation experiments showed differentiation potential along osteogenic, chondrogenic, adipogenic, and myogenic lineages. In conclusion, we propose human term placenta as an easily accessible, ample source of multipotent mesengenic progenitor cells.

Adipocytes↗