Niche-specific macrophage loss promotes skin capillary aging.

TitleNiche-specific macrophage loss promotes skin capillary aging.
Publication TypeJournal Article
Year of Publication2023
AuthorsMesa KR, O'Connor KA, Ng C, Salvatore SP, Littman DR
Date Published2023 Aug 27

All mammalian organs depend upon resident macrophage populations to coordinate repair processes and facilitate tissue-specific functions1-3. Recent work has established that functionally distinct macrophage populations reside in discrete tissue niches and are replenished through some combination of local proliferation and monocyte recruitment4,5. Moreover, decline in macrophage abundance and function in tissues has been shown to contribute to many age-associated pathologies, such as atherosclerosis, cancer, and neurodegeneration6-8. Despite these advances, the cellular mechanisms that coordinate macrophage organization and replenishment within an aging tissue niche remain largely unknown. Here we show that capillary-associated macrophages (CAMs) are selectively lost over time, which contributes to impaired vascular repair and tissue perfusion in older mice. To investigate resident macrophage behavior in vivo, we have employed intravital two-photon microscopy to non-invasively image in live mice the skin capillary plexus, a spatially well-defined model of niche aging that undergoes rarefication and functional decline with age. We find that CAMs are lost with age at a rate that outpaces that of capillary loss, leading to the progressive accumulation of capillary niches without an associated macrophage in both mice and humans. Phagocytic activity of CAMs was locally required to repair obstructed capillary blood flow, leaving macrophage-less niches selectively vulnerable to both homeostatic and injury-induced loss in blood flow. Our work demonstrates that homeostatic renewal of resident macrophages is not as finely tuned as has been previously suggested9-11. Specifically, we found that neighboring macrophages do not proliferate or reorganize sufficiently to maintain an optimal population across the skin capillary niche in the absence of additional cues from acute tissue damage or increased abundance of growth factors, such as colony stimulating factor 1 (CSF1). Such limitations in homeostatic renewal and organization of various niche-resident cell types are potentially early contributors to tissue aging, which may provide novel opportunities for future therapeutic interventions.

Alternate JournalbioRxiv
PubMed ID37662387
PubMed Central IDPMC10473701
Grant ListP30 CA016087 / CA / NCI NIH HHS / United States
R01 AI158687 / AI / NIAID NIH HHS / United States
T32 AR064184 / AR / NIAMS NIH HHS / United States
F32 AG071336 / AG / NIA NIH HHS / United States
S10 OD019974 / OD / NIH HHS / United States
S10 RR023704 / RR / NCRR NIH HHS / United States
Related Faculty: 
Steven P. Salvatore, M.D.

Pathology & Laboratory Medicine 1300 York Avenue New York, NY 10065 Phone: (212) 746-6464
Surgical Pathology: (212) 746-2700