Differential ontogeny contributes to the macrophage diversity in the peripheral nervous system

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Peripheral nerves are essential networks for both basic and advanced functions of the body. Although neurons and glial cells are the fundamental blocks of a nerve, additional resident cell types such as endothelial cells and macrophages play critical roles in maintaining nerve integrity. Among these cells, the macrophages offer homeostatic, protective, healing and pathological functions to the nerves. How they tailor themselves to coordinate such diverse functions physiologically is an active area of investigation, and demands further investigation into their unexplained in situ plasticity. Current knowledge underpins that the macrophages in the peripheral nervous system (PNS) have a single lineage that they are derived from the terminal differentiation of infiltrating monocytes. However, I recently published that a population of macrophage self-renew and repopulate in the PNS without contribution from monocytes, suggesting that not all macrophages in the PNS are terminally differentiated monocytes. Therefore, I challenge the current paradigm that the PNS macrophages are solely infiltrating monocytes. My view is endorsed by earlier demonstrations that primitive macrophages in the embryo develop from yolk-sac derived progenitor cells (YPCs), even before a monocyte is born. I hypothesize that the self-renewing PNS macrophage originates from YPCs and has distinct molecular and functional properties compared to its monocyte counterpart. The mixed presence and diverse functions of the self-renewing and infiltrating macrophage contribute to the functional dichotomy associated with the PNS macrophages. To study this hypothesis and to identify if the self-renewing macrophage has a YPC lineage, we will use transgenic animal lines that irreversibly label YPC-derived early-born macrophages with Yellow Fluorescent Protein (YFP) in the embryo under controlled conditions. To characterize the macrophage subtypes, which is central to understand their diverse physiological roles, we will employ an RNA-sequencing approach in purified populations of either self-renewing or infiltrating macrophages identified in the adult mice. The long-term goal in my laboratory is to understand how multiple cell types with complex functions coordinate each other to perform physiological tasks. My short-term goal in this proposal is to characterize the macrophage subtypes and understand how they spatially coordinate with each other, and with other cell types in the PNS, to offer homeostatic, protective and healing functions. To address this, their molecular signature, distribution ratio, and interactions with neurons, glial cells and endothelial cells in the PNS will be assessed in the steady-state conditions and during nerve regeneration. This study is an initial upfront step for my long-term research goal and will advance the knowledge of macrophage biology, and assist in devising subtype specific manipulation of these cells for future research and therapeutic applications.