Beyond Stem Cells: Self-Renewal of Differentiated Macrophages

Background Many mature cells of the body are continuously replaced, particularly in tissues that are most exposed to the environment such as cells of the immune system. The need for new cells is driven by cellular turnover during normal tissue homeostasis and is further increased upon infection. Because differentiated cells typically withdraw from the cell cycle, replacement of mature cells is generally thought to depend on differentiation of self-renewing, tissue-specific stem cells. Until recently, tissue macrophages were thought to follow such a pathway, developing from hematopoietic stem cells via bone marrow–progenitor and blood monocyte intermediates. But this view has changed of late with several observations indicating that macrophages can self-renew by local proliferation of mature differentiated cells. Advances Recent studies have demonstrated that in macrophages, differentiation and cell cycle withdrawal can be uncoupled by the inactivation of specific transcription factors. These cells can then be expanded indefinitely as functionally differentiated macrophages without tumorigenic transformation. At the same time, it became clear that mature macrophages could also expand massively in vivo in response to infections by local proliferation, independently of input from adult hematopoietic stem cells. Furthermore, several populations of tissue macrophages were found to be derived from embryonic progenitors, and macrophages can be self-maintained in adult tissues by local proliferation. Together, these recent data suggest that macrophages are mature differentiated cells that may be endowed with self-renewal capacity akin to that of stem cells. Outlook These findings challenge the classical view of tissue maintenance by adult tissue-specific stem cells and indicate that stem cell–like self-renewal mechanisms may be activated in mature differentiated cells. It will be important to determine whether the engaged pathways resemble those active in stem cells and whether they might be activated in other cell types as well. Furthermore, we need to understand how such self-renewal capacity differs from uncontrolled proliferation induced by oncogenic transformation. A first step will be to explore how macrophage proliferation is regulated in vivo: How do macrophages adapt their cell numbers to diverse tissue requirements, from near quiescence during homeostasis to massive expansion under challenge? Macrophages are present in nearly every tissue and serve important functions in immunity, cancer, metabolism, and tissue repair. The role of local macrophage proliferation in these processes has remained largely unexplored. It will be important to investigate how the consequences of macrophage accumulation by local proliferation differ from those of monocyte-derived macrophage recruitment under inflammatory conditions. The control of macrophage numbers independent of inflammatory signals may provide new opportunities for therapeutic intervention in many of these areas.