Disruption of perinatal myeloid niches impacts the aging clock of pancreatic β cells.

Perinatal expansion of pancreatic β cells is critical to metabolic adaptation. Yet, mechanisms surveying the fidelity by which proliferative events generate functional β cell pools remain unknown. We have previously identified a CCR2 myeloid niche required for peri-natal β cell replication, with β cells dynamically responding to loss and repopulation of these myeloid cells with growth arrest and rebound expansion, respectively. Here, using a timed single-cell RNA-sequencing approach, we show that transient disruption of perinatal CCR2 macrophages change islet β cell repertoires in young mice to resemble those of aged mice. Gene expression profiling and functional assays disclose prominent mitochondrial defects in β cells coupled to impaired redox states, NAD depletion, and DNA damage, leading to accelerated islets' dysfunction with age. These findings reveal an unexpected vulnerability of mitochondrial β cells' bioenergetics to the disruption of perinatal CCR2 macrophages, implicating these cells in surveying early in life both the size and energy homeostasis of β cells populations.