Characterization of naked mole‐rat hematopoiesis reveals unique stem and progenitor cell patterns and neotenic traits.

Naked mole rats (NMRs) are the longest‐lived rodents yet their stem cell characteristics remain enigmatic. Here, we comprehensively mapped the NMR hematopoietic landscape and identified unique features likely contributing to longevity. Adult NMRs form red blood cells in spleen and marrow, which comprise a myeloid bias toward granulopoiesis together with decreased B‐lymphopoiesis. Remarkably, youthful blood and marrow single‐cell transcriptomes and cell compositions are largely maintained until at least middle age. Similar to primates, the primitive stem and progenitor cell (HSPC) compartment is marked by CD34 and THY1. Stem cell polarity is seen for Tubulin but not CDC42, and is not lost until 12 years of age. HSPC respiration rates are as low as in purified human stem cells, in concert with a strong expression signature for fatty acid metabolism. The pool of quiescent stem cells is higher than in mice, and the cell cycle of hematopoietic cells is prolonged. By characterizing the NMR hematopoietic landscape, we identified resilience phenotypes such as an increased quiescent HSPC compartment, absence of age‐related decline, and neotenic traits likely geared toward longevity. Synopsis: Naked mole‐rats are the longest‐lived rodents but their hematopoietic system and contained self‐renewing stem cell populations remain poorly characterized. Combining surface marker and sequencing analysis, this resource reports the first comprehensive map of the naked mole‐rat blood system, uncovering similarities to their human counterpart during ageing. A cross‐reactive FACS antibody panel allows for purification of naked mole‐rat stem, progenitor and effector cells from blood, spleen and bone marrow.Red blood cells are produced in both bone marrow and spleen, exemplifying a neotenic trait.Enlargement of the myeloid compartment and concomitantly reduced B‐lymphopoiesis in the bone marrow resemble fetal stages of white blood cell production.CD34 marks the primitive stem and progenitor compartment, similar as in humans.An enlarged quiescent stem cell pool preserves hematopoiesis during an extended lifespan.Stem and progenitor cells feature a prolonged cell cycle in vivo, with a low metabolic profile and elevated lipid metabolism. [ABSTRACT FROM AUTHOR]