Repopulating Kupffer cells originate directly from hematopoietic stem cells.

Area of Science:

• Immunology
• Hematology
• Hepatology

Background:

• Kupffer cells (KCs) are crucial liver-resident macrophages originating from yolk-sac progenitors.
• Adult KCs self-maintain but their replenishment source after depletion was unclear.
• Existing paradigms suggested KCs repopulate from resident KCs or circulating monocytes (MOs).

Purpose of the Study:

• To elucidate the cellular origin of repopulating Kupffer cells in adult mice.
• To investigate KC origin following depletion and during chronic liver inflammation.

Main Methods:

• Utilized tissue-resident macrophage-specific and monocytic cell-specific fate-mapping mouse models.
• Employed genetic lineage tracing to identify progenitor cells involved in KC replenishment.
• Applied HSC-specific fate-mapping in a chronic liver inflammation model.

Main Results:

• Fate-mapping revealed no evidence of repopulating KCs originating from preexisting KCs or MOs.
• Following KC depletion, hematopoietic stem cells (HSCs) proliferated, mobilized, and differentiated into KCs.
• In chronic inflammation, repopulating KCs were confirmed to originate directly from HSCs.

Conclusions:

• Repopulating KCs in adult mice originate directly from hematopoietic stem cells (HSCs).
• This finding challenges the current understanding of KC cellular origins.
• Provides novel insights into KC roles in liver homeostasis and disease pathogenesis.