Pathways in the development of liver macrophages: alternative precursors contained in populations of lymphocytes and bone-marrow cells

Abstract

The origin of dividing liver macrophages during states of intense reticulo-endothelial stimulation has been studied in mice by means of the T 6 marker chromosome. The cells were isolated for cytological analysis by means of Garvey's technique of collagenase and trypsin digestion. During the proliferative phase of graft-versus-host (GVH) reaction in the strain combination C 57 BL $\rightarrow $ (C 57 BL $\times $ CBA-T 6 T 6)F$_{1}$, practically all liver macrophages in mitosis were of donor karyotype, even when relatively pure suspensions of thoracic duct small lymphocytes were used as the donor cells. Several lines of evidence established that the dividing cells analysed were part of a macrophage response. The isolated cells in mitosis had macrophage characteristics which reflected the cell proliferation examined in histological sections. This proliferation was largely restricted to the liver sinusoids and to cells with phagocytic properties. The same proportion of these cells appeared to be actively phagoctyic before their arrest in metaphase by Colcemid during GVH reaction as was found in normal mice. Furthermore, more than 70% of the liver sinusoidal cells which incorporated $^{3}$H-thymidine were demonstrably phagocytic before and/or after labelling. Liver macrophage proliferation was greatly depressed by splenectomy 24 h after injection of donor cells, although cells of donor karyotype were still predominant. Similar techniques have been applied to syngeneic radiation chimaeras-(CBA $\times $ CBA-T 6 T 6)F$_{1}$ mice 'repopulated' with CBA-T6T6 lymphocytes and CBA bone marrow. When Corynebacterium parvum vaccine was applied as a stimulant, two-thirds of dividing liver macrophages were found to be of lymphocyte origin and one-third or less derived from a precursor in bone marrow cells. Using partial hepatectomy to stimulate macrophage proliferation in these chimaeras, however, it was found that the overwhelming majority were derived from the bone-marrow precursor. The phagocytic property of the majority of proliferating cells was established by combined colloid and $^{3}$H-thymidine labelling. It is concluded that liver macrophages derived from either of two different precursors in populations of recirculating lymphocytes and bone marrow cells respectively can proliferate preferentially, according to the nature of the reticulo-endothelial stimulus. Evidence from a variety of sources supports the contention that the bone-marrow precursor cell represents the major source of 'normal' macrophages. Whether the precursor amongst thoracic duct cells is identifiable with any previously recognized category of lymphocyte is not yet known. Its utilization has only been detected so far during conditions of intense reticuloendothelial stimulation.