Targeting BIRC6 rejuvenates hematopoietic stem cell aging and immunosenescence
TL;DR
It is revealed that regulatory T cells within the bone marrow microenvironment actively safeguard the survival of aged HSCs via a previously uncharacterized signaling pathway, and targeted BIRC6 inhibition in HSCs using antibody-conjugated lipid nanoparticle-encapsulated antisense oligonucleotides (LNP-ASOs) significantly reverses hematopoietic-immune aging phenotypes and ameliorates age-associated immune dysfunction in middle-aged mice.
Abstract
Immunosenescence represents a central hallmark of organismal aging, characterized by a progressive decline in immune function, which compromises host defense and accelerates systemic aging. Hematopoietic stem cell (HSC) aging is a key contributor to this process, characterized by aberrant expansion, myeloid-biased differentiation, and impaired self-renewal, culminating in hematopoietic-immune imbalance. Although the expansion and survival advantages of aged HSCs have been well-demonstrated, the underlying mechanisms remain elusive. Here, we reveal that regulatory T cells (Tregs) within the bone marrow (BM) microenvironment actively safeguard the survival of aged HSCs via a previously uncharacterized signaling pathway. We identify a novel aged HSC subpopulation characterized by high expression of Baculoviral IAP Repeat Containing 6 (BIRC6), an apoptosis inhibitor. This BIRC6-high subpopulation is markedly expanded in aged mice and recapitulates the hallmarks of HSC aging. Mechanistically, cAMP derived from BM Tregs activates the PKA–CREB pathway in HSCs, activating Birc6 transcription, which reduces apoptotic priming in aged HSCs, thereby promoting hematopoietic-immune imbalance. Strikingly, targeted BIRC6 inhibition in HSCs using antibody-conjugated lipid nanoparticle-encapsulated antisense oligonucleotides (LNP-ASOs) significantly reverses hematopoietic-immune aging phenotypes and ameliorates age-associated immune dysfunction in middle-aged mice. LNP-ASO treatment dramatically rebalances immune cell production, reduces immunosenescence markers, and enhances vaccine responses in middle-aged mice. More importantly, this strategy was also effective in HSCs from middle-aged human donors, highlighting its potential for clinical translation. These findings elucidate a key microenvironmental pathway (Treg–cAMP–PKA–CREB–BIRC6) driving HSC aging and offer a novel strategy to ameliorate the aged hematopoietic system and combat age-related immune decline.