The hematopoietic landscape at single-cell resolution reveals unexpected stem cell features in naked mole-rats

SUMMARY Naked mole-rats are the longest-lived rodents endowed with resistance to cancer and age-related diseases, yet their stem cell characteristics remain enigmatic. We profiled the naked mole-rat hematopoietic system down to single-cell resolution, and identified several unique features likely contributing to longevity. In adult naked mole-rats red blood cells are formed in spleen and marrow, a neotenic feature beneficial for hypoxic environments and to prevent anemia. Platelet numbers are lower compared to short-lived mice, which may preclude age-related platelet increase and thrombosis. T cells mature in thymus and lymph nodes, providing a supply of T cells after age-related thymus involution. The pool of quiescent stem cells is higher than in mice, and HSCs overexpress an oxidative phosphorylation signature, revealing a new paradigm of stem cell metabolism to benefit longevity and oppose oncogenesis. Our work provides a platform to study immunology and stem cell biology in an animal model of healthy aging. HIGHLIGHTS Flow cytometry labelling panel to purify viable naked mole-rat HSPCs The spleen as the major site of erythropoiesis in the naked mole-rat Naked mole-rats show extrathymic T-cell development under homeostatic conditions Naked mole-rat hematopoietic stem cells (HSCs) have high OXPHOS activity