Pathology of Genetically Engineered and Other Mutant Mice. Группа авторов

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7 Hematopoietic and Lymphoid Tissues

       Harm HogenEsch and John P. Sundberg

Introduction

      Hematopoiesis refers to the production of erythrocytes, leukocytes, and platelets from hematopoietic stem cells (HSCs), a population of self‐renewing cells that can give rise to all blood cell lineages. HSCs are needed throughout the life of mice to maintain blood cell populations because of their relatively short lifespan. HSCs are found in the bone marrow and spleen of adult mice and can be recruited to other extramedullary tissues when there is increased demand for hematopoiesis.

      The hemopoietic system is derived from the mesoderm in three waves during embryonal development. The first and second waves occur in the yolk sac of the embryo beginning at embryonal day (ED) 7, and generate blood cells that supply the developing embryo including macrophages involved in tissue remodeling [1]. The definitive HSCs, which can reconstitute the entire hematopoietic system of a lethally irradiated adult mouse, are generated in the third wave around ED 10.5 from the hemogenic endothelium of the dorsal aorta of the aorta‐gonad‐mesonephros (AGM) tissue. The generation of HSCs is dependent on proinflammatory cytokines secreted by macrophages in the arterial wall and by catecholamines supplied by the sympathetic nervous system in the developing embryo [2, 3]. The HSCs migrate from the AGM to the fetal liver where they undergo marked proliferation between ED 11 and ED 16. Additional HSCs are supplied to the fetal liver by the vitelline and umbilical arteries. From the fetal liver, HSCs move to the fetal spleen from around ED15.5 until a few weeks after birth. Hemopoietic stem cells in the spleen of adult mice are mostly committed to erythropoiesis. In addition, HSCs begin to populate the bone marrow starting at ED17.5. They undergo a rapid expansion in the bone marrow during the first three weeks after birth after which they become quiescent [1].

      We describe here the pathology of the hemopoietic and lymphoid tissues with an emphasis on changes in mice with spontaneous and genetically engineered mutations. A detailed review of the pathology of these tissues in mice and rats was recently published as part of the INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) [4].

Bone Marrow

      The bone marrow occupies the cavities of the trabecular meshwork of the axial and long bones. It is highly vascularized and supplied by nerves, but it lacks lymphatic drainage. The bone marrow forms a network of hemopoietic and nonhemopoietic cells, including endothelial cells, pericytes, fibroblasts, and osteoblasts. Together, these cells form a niche, a microenvironment for HSCs that controls their self‐renewal and differentiation [5]. The HSCs generate progenitor cells that differentiate into erythrocytes, leukocytes, including immature B lymphocytes, and platelets. In addition to its major role in generating blood cells, the bone marrow is also the site where populations of plasma cells and memory T cells reside following their induction in secondary lymphoid organs.

       Examination of bone marrow: Routine assessment of the bone marrow is performed on sections of bones following formalin fixation and decalcification. Decalcification is usually achieved with organic acids such as formic acid or with chelating agents such as ethylenediaminetetraacetic acid (EDTA) solution. The latter procedure takes longer but is preferred for immunohistochemistry because of enhanced antigen preservation. The knee joint with the distal femur and proximal tibia and sternum are good choices. Light microscopy of H&E‐stained sections, preferably less than 4 μm thick, can assess overall cellularity, ratio of erythroid to myeloid precursors, and number of megakaryocytes. Examination of smears or cytospin preparations of bone marrow cells can provide a more detailed analysis of the cellular composition of the bone marrow. Cell suspensions can be obtained by flushing the long bones with a 25G needle and syringe after removing the ends (epi‐ and metaphyses). In depth analysis of the cellular composition of bone marrow and the different maturation stages of blood cell lineages requires flow cytometry of cells labeled with fluorochrome‐conjugated antibodies.

       Hypoplasia and aplasia: Mutations or chemical treatments that induce DNA damage or interfere with cell division will induce bone marrow aplasia, a general loss of all hematopoietic lineages. Hematopoietic cells are absent, and bone marrow space is filled with venous sinuses and a few adipocytes (Figure 7.1). Such changes are often associated with a reduction of the red pulp of the spleen. Loss of specific lineages may be seen with genetic deletion of growth factors. A selective decrease of erythropoiesis is associated with chronic inflammation. There is increased myelopoiesis and an increase of hemosiderin.