摘要:

AbstractThe constant and appropriate production of megakaryocytes, and subsequently platelets, is critical for maintenance of hemostasis. Inadequate megakaryopoiesis and/or thrombopoiesis can lead to serious bleeding disorders. The humoral factors regulating these processes have been the subject of study for several decades. Although many cytokines have been shown to influence megakaryocyte development and platelet production, none appeared to do so in a lineage‐dominant fashion analogous to the situation with erythrocyte and neutrophil production. More recently, a ligand for the hematopoietic cytokine receptor encoded by the c‐mplgene (Mpl ligand) has been shown to have profound effects on megakaryocyte growth and development. These effects appear to include the expansion of megakaryocyte progenitors (i.e. megakaryocyte‐colony stimulating activity), and induction of megakaryocyte maturation to the point of platelet production (i.e. thrombopoietin). Administration of recombinant Mpl‐ligand to rodents or primates treated with myelosuppresive agents abrogates or alleviates the severity and the duration of the resultant thrombocytopenias. The in vitro and in vivo data to date indicate that this new cytokine holds tremendous promise as a therapeutic agent for the treatment of thrombocytopenia associated with cancer th

ISSN:1066-5099    

DOI:10.1002/stem.5530130602

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractPlatelet transfusions have long had an important role in the treatment of patients with thrombocytopenia due to disease or myelotoxic treatment or in patients with reduced platelet function. However, platelet transfusions are associated with numerous risks, both immunologic (e.g., transfusion reactions, alloimmunization, immunosuppression) and infectious (e.g., viral, bacterial). In addition, several laboratory and clinical factors can influence post‐transfusion platelet recovery. Recent technological advances have introduced the potential for using alternatives to platelet transfusions, such as cytokines or platelet substitutes, which may avoid the risks of transfusion. Platelet development from megakaryocytes is a process that is highly regulated by cytokines and animal research suggests that selected cytokines involved in this process may be useful in the treatment of thrombocytopenia. Newer developments, including the utilization of recombinant cytokines with relatively selective stimulation of platelet production (e.g., interleukin 6 [IL‐6]) and the recent discovery of a megakaryocyte colony stimulating factor (thrombopoietin), represent major therapeutic opportunities in the treatment of thrombocytopenia. Platelet substitutes, e.g., thromboerythrocytes, also show promise in the management of platelet deficienc

ISSN:1066-5099    

DOI:10.1002/stem.5530130603

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractWith the help of stem cell reinfusion and hematopoietic growth factors, it is possible to get up to a ten‐fold dose increase for certain chemotherapeutic drugs. A number of reasons may have made high‐dose chemotherapy less dangerous and therefore more acceptable in a more upfront treatment setting. One of these is the addition of peripheral stem cell harvest obtained after mobilization with a hematopoietic growth factor alone or after chemotherapy followed by a hematopoietic growth factor, which seems to result in a faster recovery of neutrophils and platelets compared to bone marrow reinfusion alone. The combination of various hematopoietic growth factors could potentially improve hematopoietic recovery of the high‐dose chemotherapy regimen. The relevance of tumor cells sometimes present in the reinfused hematopoietic stem cells is as yet unknown.High‐dose chemotherapy may be interesting for a number of solid tumors such as nonseminomatous testicular carcinoma, breast carcinoma in the metastatic and adjuvant setting, ovarian carcinoma, tumors of young adults such as Ewing sarcoma and small cell lung carcinoma. In patients with refractory nonseminomatous testicular cancer there have been a number of studies performed with high‐dose chemotherapy showing a 15% complete and prolonged remission. For other tumor types and settings it will be necessary to perform randomized studies before firm conclusions can be drawn. For example, this is especially important for patients with breast carcinoma with more than three positive axillary lymph nodes. Preliminary data from various groups compared to historical controls treated with standard adjuvant chemotherapy show favorable results of adjuvant chemotherapy containing high‐dose chemotherapy. Many relatively small nonrandomized studies are performed in various stages of disease for ovarian carcinoma. Although there are long‐term survivors reported it is currently difficult to draw firm conclusions. The potentially safer therapy of high‐dose chemotherapy may reveal in the near future the role of high‐dose chemotherap

ISSN:1066-5099    

DOI:10.1002/stem.5530130604

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractThe development of serum‐free systems for the maintenance and expansion of both primitive and committed hematopoietic progenitors has numerous applications in both basic and clinical research. Many different media have been tested and refined over the years, and current formulations now yield results similar to those observed with fetal bovine serum‐based medias. Using these serum‐free culture systems, the impact of the cell microenvironment and individual growth factors on primitive and maturing stem cells have both been studied. The utility of progenitor populations expanded ex vivo under serum‐free conditions is under invest

ISSN:1066-5099    

DOI:10.1002/stem.5530130605

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractHuman umbilical cord blood contains abundant primitive and committed hematopoietic progenitors and has been used as an alternative source of reconstituting hematopoietic stem cells. Recent advances in the understanding of molecular aspects of multiple diseases and improvements in technology associated with prenatal diagnosis now allow the in utero identification of many genetic diseases affecting the hematopoietic system. Advances in technology raise the potential for genetic correction and subsequent transplantation of autologous cord and placental blood hematopoietic stem cells into affected patients prior to expression of the disease phenotype. This review will summarize the recent data on advances in prenatal diagnosis, characterization of the biology of cord blood stem cells, and efforts at developing methods for genetic transduction of cord blood hematopoietic stem/progenitor cells.

ISSN:1066-5099    

DOI:10.1002/stem.5530130606

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractThe recent discovery of multilineage donor leukocyte microchimerism in allograft recipients up to three decades after organ transplantation implies the migration and survival of donor stem cells within the host. It has been postulated that in chimeric graft recipients, reciprocal modulation of immune responsiveness between donor and recipient leukocytes may lead, eventually, to the induction of mutual immunologic nonreactivity (tolerance). A prominent donor leukocyte, both in human organ transplant recipients and in animals, has invariably been the bone marrow‐derived dendritic cell (DC). These cells have been classically perceived as the most potent antigen‐presenting cells but evidence also exists for their tolerogenicity. The liver, despite its comparatively heavy leukocyte content, is the whole organ that is most capable of inducing tolerance. We have observed that DC progenitors propagated from normal mouse liver in response to GM‐CSF express only low levels of major histocompatibility complex (MHC) class II antigen and little or no cell surface B7 family T cell costimulatory molecules. They fail to activate resting naive allogeneic T cells. When injected into normal allogeneic recipients, these DC progenitors migrate to T‐dependent areas of host lymphoid tissue, where some at least upregulate cell surface MHC class II. These donor‐derived cells persist indefinitely, recapitulating the behavior pattern of donor leukocytes after the successful transplantation of all whole organs, but most dramatically after the orthotopic (replacement) engraftment of the liver. A key finding is that in mice, progeny of these donor‐derived DC progenitors can be propagated ex vivo from the bone marrow and other lymphoid tissues of nonimmunosuppressed spontaneously tolerant liver allograft recipients.In humans, donor DC can also be grown from the blood of organ allograft recipients whose organ‐source chimerism is augmented with donor bone marrow infusion. DC progenitors cannot, however, be propagated from the lymphoid tissue of nonimmunosuppressed cardiac‐allografted mice that reject their grafts. These findings are congruent with the possibility that bidirectional leukocyte migration and donor cell chimerism play key roles in acquired transplantation tolerance. Although the cell interactions are undoubtedly complex, a discrete role can be identified for DC under well‐defined experimental conditions. Bone marrow‐derived DC progenitors (MHC class II+, B7–1dim, B7–2−) induce alloantigen‐specific hyporesponsiveness (anergy) in naive T cells in vitro. Moreover, costimulatory molecule‐deficient DC progenitors administered systemically prolong the survival of mouse heart or pancreatic islet allografts. How the regulation of donor DC phenotype and function relates to the balance between the immunogenicity and tolerogenicity of organ allogr

ISSN:1066-5099    

DOI:10.1002/stem.5530130607

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractNeural crest cells are derived from a population of multipotent stem cells within the neural tube. They emerge shortly after neural tube closure, migrate extensively in the embryo and localize in numerous sites, where they differentiate into neurons and glia of the peripheral nervous system, cartilage and bone of the face, melanocytes and various other cell types. This review summarizes recent experiments from our laboratory delineating the origin and lineage of avian neural crest cells. Neural crest cells arise from the ectoderm, which also gives rise to presumptive epidermal, placodal and neural tube cells. Fate mapping experiments have demonstrated that the neural crest arises at the juncture between presumptive epidermis and the neural plate. Inductive interactions between these two early tissues can generate neural crest cells, suggesting that signals travel through the epidermis to generate neural crest cells prior to neural tube closure. Injection of lineage tracer into individual cells reveals that a single neural fold can form all ectodermal derivatives (i.e., epidermis, neural tube, neural crest). Even after neural tube closure, neuroepithelial cells have the capacity to form multiple neural crest and neural tube derivatives, including both dorsal and ventral phenotypes, suggesting that neural tube and neural crest cells share a common precursor. Further evidence that neural crest and neural tube cells are intimately related comes from experiments in which the cranial neural folds are ablated. The remaining neural tube cells have the capacity to regulate, at least for a limited time, to compensate for missing neural crest cells. These experiments suggest that the early neuroepithelium has no clear segregation with respect to the neural tube or neural crest. With time, dorsalizing and ventralizing signals may cause neural tube cells to acquire specific cell fates.

ISSN:1066-5099    

DOI:10.1002/stem.5530130608

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractThe clinical application of recombinant human G‐CSF in patients with acute myeloid leukemia (AML) has been controversial because it stimulates the in vitro proliferation of leukemic cells. In order to explore the possibility of predicting in vivo leukemic proliferation after G‐CSF administration to AML patients by using in vitro assays, we investigated the leukemic blasts of 30 AML patients, including 14 patients who received G‐CSF for severe infection associated with neutropenia following chemotherapy (G‐CSF group) and 16 patients who did not (control group). Of the 14 patients in the G‐CSF group, 9 showed an increase of leukemic blasts in the peripheral blood during G‐CSF administration, while 11 of the 16 control patients developed leukemic resurgence. In the G‐CSF group, the frequency of leukemic resurgence among patients whose blasts showed dose‐dependent proliferation after addition of G‐CSF to cultures was similar to that among patients whose blasts did not. In addition, there were no significant differences between the G‐CSF and control groups in [3H]thymidine incorporation by leukemic cells and leukemic colony formation after the addition of G‐CSF to cultures. The G‐CSF receptor affinity of leukemic blasts was significantly higher in the patients with leukemic resurgence (mean dissociation constant [Kd]: 55 pM in the G‐CSF group and 63 pM in the control group) than in those without it (101 pM and 96 pM, respectively), and the number of G‐CSF receptors per cell was significantly lower when leukemic resurgence occurred (200 in the G‐CSF group and 260 in the control group) than when it did not (3400 and 3030, respectively).Immunophenotyping (for CD2, CD7, CD10, CD13, CD19, CD33, CD34, CD71, HLA‐DR, glycophorin A and the G‐CSF receptor) revealed no significant differences between blasts from the patients with and without leukemic resurgence in the G‐CSF group.Thus, we conclude that the in vivo leukemic resurgence during G‐CSF administration after chemotherapy for AML was not correlated with the in vitro responsiveness of leukemic blasts to this cytokine or with blast phenotyping data. Leukemic resurgence is likely to occur in patients whose leukemic blasts have fewer numbers of G‐CSF receptors with a high affinity irrespe

ISSN:1066-5099    

DOI:10.1002/stem.5530130609

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractStromal cells are believed to regulate hematopoiesis through direct cell‐cell contact interactions and the release of growth factors. Many questions remain, however, about their lineage derivation and functional heterogeneity. We have previously shown that the adherent nontransformed, nonimmortalized murine bone marrow stromal cell population consists of three cell types which could be grown separately in vitro. Based on the phenotype characterization and expression of surface antigens, we proposed a classification listing for murine bone marrow stromal cells as macrophages, endothelial‐like cells and myofibroblasts that display smooth muscle‐like characteristics in culture.The present study describes the ability of each of these freshly isolated separated murine stromal cell populations to support the growth of primitive hematopoietic stem cells previously characterized as highly enriched in long‐term repopulating cells (LTRC). Of the three stromal cell types tested only the myofibroblasts were capable of support for multilineage hematopoiesis derived in vitro from LTRC in a cloning ring culture system.Endothelial‐like cells had an inhibitory effect on the proliferation of LTRC and their descendant cells that was induced by exogenous growth factors. This inhibitory activity was present in a low molecular weight filtrate of endothelial‐like cells culture medium.This suggests an essential role for marrow stroma myofibroblasts in the support of proliferation of hematopoietic cells at the stage of early divisions of primitive hematopoietic stem cells and endothelial‐like cells as negative regulators of this

ISSN:1066-5099    

DOI:10.1002/stem.5530130610

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractWe demonstrated recently a decreased number, concentration and proliferative activity of colony forming units‐spleen day 8 (CFU‐Sd8) in the bone marrow of the hereditarily anemic Belgrade Laboratory (b/b) rat. The main consequence of the genetic defect in the b/b rat is impaired intracellular transport of iron resulting in altered hemopoietic stem and progenitor cell compartments. In this study, the seeding efficiency (f) for normal and b/b rat bone marrow CFU‐Sd8 was determined in a “rat to mouse” CFU‐S assay. There were no differences in f values for normal and b/b rat bone marrow CFU‐Sd8, indicating that the severe anemia and consequent metabolic alterations did not affect f in the b/b rat. The calculation of CFU‐Sd8 concentration per 105normal rat bone marrow cells using f as a correction factor revealed a value similar to that found for populations of bone marrow cells defined by phenotypes Ox7+(20%), Ox22−, W3/13dim, considered to be characteristic of CFU‐S. The results revealed the usefulness of the “rat to mouse” assay for the determination of rat

ISSN:1066-5099    

DOI:10.1002/stem.5530130611

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY