ABSTRACT
After birth, the bone marrow (BM) is the principal site of hematopoiesis in mammals. Thus, a large number of newly formed blood cells must penetrate the wall of BM microvessels to enter the circulation. In addition, the BM appears to function as a lymphoid organ and is also part of the macrophagal system. Subsets of circulating lymphocytes and other cells of the immune system continuously home to the BM. However, neither the mechanisms of blood cell migration to and from the BM nor its precise role in the immune system are well understood. One reason for the relative paucity of data on BM physiology is the fact that normal BM is surrounded by thick cortical bone that impedes direct observation and experimental manipulation. One notable exception is the calvaria of the murine skull where hematopoietically active BM is only covered by a thin lamella of bone that is sufficiently translucent to allow a detailed in situ analysis of the BM microcirculation by epi-fluorescence microscopy. Here, we review our current knowledge of the anatomic, hemodynamic, and endothelial properties of the specialized microvascular bed within murine skull BM. In addition, we summarize recent studies on the molecular mechanisms that mediate the homing of circulating hematopoietic progenitor cells to the BM, an event that is critical for the success of BM transplantations.
Subject(s)
Bone Marrow/physiology , Capillaries/physiology , Animals , Bone Marrow/blood supply , Bone Marrow Transplantation , Cell Adhesion , Endothelium, Vascular , Hematopoietic Stem Cells/physiology , Hemodynamics , Humans , Mammals , Mice , Skull , Vascular Cell Adhesion Molecule-1/physiologyABSTRACT
The adhesive mechanisms allowing hematopoietic progenitor cells (HPC) homing to the bone marrow (BM) after BM transplantation are poorly understood. We investigated the role of endothelial selectins and vascular cell adhesion molecule-1 (VCAM-1) in this process. Lethally irradiated recipient mice deficient in both P-and E-selectins (P/E-/-), reconstituted with minimal numbers (
Subject(s)
Bone Marrow Transplantation/physiology , Bone Marrow/physiology , E-Selectin/physiology , Hematopoietic Stem Cells/physiology , P-Selectin/physiology , Vascular Cell Adhesion Molecule-1/physiology , Animals , Antibodies, Monoclonal/pharmacology , Cesium Radioisotopes , Colony-Forming Units Assay , Crosses, Genetic , E-Selectin/genetics , Female , Hematopoietic Stem Cells/cytology , Male , Mice , Mice, Inbred C57BL , Mice, Inbred Strains , Mice, Knockout , Neutropenia/physiopathology , P-Selectin/genetics , Splenectomy , Survival Rate , Vascular Cell Adhesion Molecule-1/immunologyABSTRACT
We have used intravital microscopy to study physiologically perfused microvessels in murine bone marrow (BM). BM sinusoids and venules, but not adjacent bone vessels, supported rolling interactions of hematopoietic progenitor cells. Rolling did not involve L-selectin, but was partially reduced in wild-type mice treated with antibodies to P- or E-selectin and in mice that were deficient in these two selectins. Selectin-independent rolling was mediated by alpha4 integrins, which interacted with endothelial vascular cell adhesion molecule (VCAM)-1. Parallel contribution of the endothelial selectins and VCAM-1 is not known to direct blood cell trafficking to other noninflamed tissues. This combination of constitutively expressed adhesion molecules may thus constitute a BM-specific recruitment pathway for progenitor cells analogous to the vascular addressins that direct selective lymphocyte homing to lymphoid organs.
Subject(s)
Bone Marrow/physiology , Cell Movement , E-Selectin/metabolism , Hematopoietic Stem Cells/physiology , P-Selectin/metabolism , Vascular Cell Adhesion Molecule-1/metabolism , Animals , Bone Marrow/metabolism , Endothelium, Vascular/metabolism , Endothelium, Vascular/physiology , Female , Fluorescent Dyes/metabolism , Frontal Lobe/anatomy & histology , Hemodynamics , L-Selectin/biosynthesis , Male , Mice , Mice, Inbred C57BL , Microcirculation , Rhodamine 123 , Rhodamines/metabolism , Skull/anatomy & histology , VenulesABSTRACT
The authors report the results of the treatment according to the programs BFM-ALL-90 and BFM-AML-83 and 87. A total of 110 children with acute lymphoblastic leukemia (ALL) and 35 with acute myeloblastic leukemia (AML) were treated with remission rate 94.5% and 74.5%, respectively. Under programmed treatment of ALL the recurrences occurred in 12.2% against 46% of the cases in nonprogrammed treatment. 2-year survival made up 75% and 47.3%, respectively. Among AML cases there were frequently prognostically unfavorable ones and patients with neuroleukemia this dictating the necessity of the treatment intensification and irradiation of the skull in AML. Improvement of adjuvant therapy is a must in advance of acute leukemia treatment.
Subject(s)
Leukemia, Myeloid, Acute/therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Child , Combined Modality Therapy , Critical Care , HumansABSTRACT
Bone marrow granulocytic-macrophagal precursors (GMP) and fibroblastic precursors (FP) were measured in 235 children with acute lymphoblastic leukemia (ALL) receiving polychemotherapy (PCT) in progression of the disease. A total of 408 culture investigations were conducted. PCT proved to exert different effects on hemopoiesis during the first acute ALL period and remission. In the former period the target for PCT were blast cells, the course of induction therapy increased the number of GMP, FP and early granulocytic cells. In recurrent ALL the sensitivity of GMP to PCT grew, while FP remained intact. PCT performed in remission resulted in gradual suppression of granulocytopoiesis, GMP beginning from the second remission year. The treatment discontinuation on remission year 3-5 produced enhancement of granulocytosis by all parameters.
