Endothelial mTOR maintains hematopoiesis during aging.

Area of Science:

• Hematology
• Aging Biology
• Stem Cell Research

Background:

• Aging impairs hematopoietic stem and progenitor cell (HSPC) function.
• Bone marrow endothelial cells (BMECs) play a crucial role in maintaining the hematopoietic stem cell niche.
• Age-related changes in BMECs can negatively impact HSPC behavior.

Purpose of the Study:

• To investigate the role of mammalian target of rapamycin (mTOR) signaling in aged bone marrow endothelial cells (BMECs).
• To determine if endothelial-specific mTOR inhibition influences hematopoietic aging.
• To elucidate the mechanism by which BMEC niche dysfunction contributes to hematopoietic aging.

Main Methods:

• Conditional deletion of mTOR in endothelial cells (ECs) of young mice (mTOR(ECKO)).
• Assessment of HSPC function and phenotype in mTOR(ECKO) mice.
• Transcriptional profiling of HSPCs from mTOR(ECKO) and aged mice.
• Serial transplantation experiments exposing wild-type HSPCs to mTOR(ECKO) microenvironments.

Main Results:

• Aging reduces mTOR signaling in BMECs, contributing to impaired niche activity.
• Endothelial-specific mTOR deletion (mTOR(ECKO)) in young mice induced aged phenotypes in their HSPCs.
• HSPCs from mTOR(ECKO) mice showed transcriptomes resembling those of aged HSPCs.
• Exposure of wild-type HSPCs to an mTOR(ECKO) microenvironment recapitulated aging-associated phenotypes.

Conclusions:

• Decreased mTOR signaling in BMECs is a key factor in age-related hematopoietic decline.
• Endothelial cell-derived signals critically instruct hematopoietic stem cell aging.
• Targeting endothelial mTOR signaling may offer therapeutic avenues for age-related hematopoiesis dysfunction.