Discovery of fully differentiated macrophage populations with stem cell like characteristics
Stem Cell Like Renewal of Macrophage Populations
By definition stem cells are undifferentiated cells that are capable of maturing into many different cell types depending upon their local environment. When stem cells divide, a portion of the new cells continue to mature into specialized cells. But, a portion of the new cells do not mature. They maintain their immature stem cell characteristics.
Dogma, until recently, was that the resulting completely mature, differentiated cells are unable to reproduce themselves to sustain their population. Specialized tissues were all thought to rely upon tissue-specific adult stem cells for their renewal and repair. Adult stem cells are partially matured stem cells committed to becoming specific tissues.
This accepted definition of stem cells is challenged by recent studies of resident macrophage populations in most body tissues. One such population is brain specific macrophage-like cells named microglia. Microglia is derived from embryonic progenitors in the yolk sac long before the appearance of stem cells in bone marrow that replenish circulating white and red blood cells.
The brain possesses all of the microglia it needs for a lifetime of defense at birth. Fully mature, differentiated microglia massively expands it population under circumstances of stress and infection without the help of neural stem cells. The adult brain contains neural stem cells but they only produce new neurons, oligodendrocytes and astrocytes.
Immune system macrophages distributed in tissues throughout the rest of the body play a role in local metabolism and are essential to tissue repair, immunity against pathogens and cancer. They are phagocytic cells with high lysosome activity. They, like microglia of the brain, clean up debris as cells die.
Recent studies of a wide range of tissue macrophages from liver, skin, lung, spleen, adipose tissue, cardiac tissue, pleura and peritoneum demonstrate that the cell cycle withdrawal accompanying maturation of tissue macrophages can be reversed without them becoming tumorigenic. Like stem cells, tissue macrophages are fully capable of self-renewal.
First Responders and the Clean-up Crew
Older studies concluded all immune system macrophages developed from monocytes, which in turn are partially mature bone marrow stem cells. Lineage tracing experiments with cell markers expressed only in descendent cells, now suggest than many adult macrophage populations are derived from embryonic progenitors rather than from bone marrow monocytes.
Body tissues are seeded during early embryonic development with fetal liver and yolk sac cells that develop into tissue-specific resident macrophages. These cells occupy the tissue before bone marrow blood formation begins. Unlike blood monocytes that die in a few days embryonic tissue macrophages can persist throughout a lifetime.
Each tissue induces special properties in its macrophage population. Like stem cells, tissue macrophages respond to their local environment. Also like stem cells, tissue macrophages establish and maintain their population size by reentering the cell cycle as fully mature cells to reproduce themselves. Proliferation sustains the population under homeostatic conditions and replenishes it after severe depletion by stressful conditions and infection.
Tissue macrophages are the first responders to infection, the first line of defense. They react by massively proliferating and attacking pathogens. Monocytes also defend against a broad range of pathogens, but they enter tissues during infection from the blood stream. Once in the tissue they transform into macrophages to assist the tissue macrophages destroy the intruders. Monocyte derived macrophages are important to finishing the kill and repairing the damage.
With severe infection there is a great loss of tissue macrophages. Recovery of the tissue specific population occurs by expansion of the remaining macrophages of embryonic origin with little to no permanent contribution by macrophages of monocyte descent.
How to Distinguish the Two Macrophage Populations
Transcription factor programs for reading out DNA of the two types of macrophages, embryonic and monocyte-derived, are under active investigation. Early results indicate that regulation of molecular pathways is different in these two types of macrophages. It appears these methods will permit investigators to distinguish them as separate cell types with unique responses to the challenges in their environment.
It is of therapeutic importance to determine whether regulation of tissue macrophages, an accessible population, is similar to regulation of brain microglia. Brain microglia experiments are hampered by the blood brain barrier. Yet, many degenerative conditions of the brain, including Alzheimer’s disease, have a strong, unfavorable microglial inflammatory component.
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