Bye-bye My-HSC: Antibody Depletion of Myeloid-biased Stem Cells Revitalizes Aged Blood and Boosts Immunity

Hematopoietic stem cells (HSCs) are responsible for the sustained generation of functional blood and immune cells throughout mammalian life, maintaining the balance between myeloid and lymphoid lineages. During aging, however, HSCs exhibit a skewed differentiation toward the myeloid lineage, leading to reduced production of lymphoid cells.¹  This imbalance is pivotal in age-related immune dysfunction, which manifests as chronic inflammation and a higher risk of infection, as well as increased prevalence of anemia and other hematological disorders among the elderly.²  Mitigating these negative features and reverting hematopoiesis to a more “youthful” state has therefore emerged as an area of intense interest within the HSC field.

Various approaches to rejuvenating HSCs have been tried, some with promising results, including epigenetic reprogramming,³  metabolic/mitochondrial intervention,⁴  and restoration of the bone marrow niche.⁵  These prior interventions have aimed to counteract the consequences of blood aging. However, the alternative approach — depleting the age-associated HSCs to “rejuvenate” the system by allowing “young” HSCs to expand — has until now been elusive. It has been shown that myeloid-biased HSCs (my-HSCs) are intrinsically different from balanced HSCs (bal-HSCs),^6,7  including in their expression of cell surface antigens, providing a potential avenue for intervention.

In a recent study, Jason Barzel Ross, MD, PhD, and colleagues demonstrated that treatment of mice using antibodies aiming to selectively deplete my-HSCs could reverse age-associated biased HSC differentiation and restore immunity in mice. To first identify cell surface markers that are differentially expressed on my-HSCs, the authors conducted a systematic analysis of HSCs from older versus young mice, as well as my-HSCs versus bal-HSCs. Following protein-level validation using flow cytometry, the researchers selected CD150, CD62p, and NEO1 as candidate targets for in vivo antibody depletion of my-HSCs.

By optimizing antibody-conditioning protocols, the authors found that combining antibodies against CD150, CD62p, or NEO1 with CD47 and KIT achieved higher depletion efficiency compared to individual antibodies. Encouragingly, following my-HSC depletion, the treated mice exhibited reduced frequency of myeloid progenitors in their bone marrow, including common myeloid progenitors (CMPs), granulocyte-monocyte progenitors (GMPs), megakaryocyte progenitors (MkPs), and megakaryocyte-erythrocyte progenitors (MEPs). The authors also noted that treated mice exhibited increased frequency of common lymphoid progenitors (CLPs) in their bone marrow. Furthermore, the transcriptional landscape of HSCs after antibody conditioning of aged mice showed a shift toward the profile of young and bal-HSCs.

To prove the treated HSCs are truly rejuvenated, the authors performed stem cell transplantations with myeloid-depleted HSCs to functionally assess HSC potential. HSCs following my-HSC depletion reconstituted hematopoiesis with reduced myeloid-to-lymphoid cell ratios in peripheral blood, confirming that depletion of my-HSC led to functional changes in HSC potential and fate.

Dr. Ross and his colleagues next investigated the effects of my-HSC depletion on immune function, comparing young-adult mice with aged mice, either subjected or not subjected to antibody conditioning. Following my-HSC antibody depletion, aged mice showed increased frequencies of lymphocyte progenitors after one week and persisting for around four months. In concordance with this, my-HSC depletion led to increased production of both naive T cells and mature B cells in aged mice.

Higher expression of exhaustion markers in lymphocytes and elevated levels of pro-inflammatory mediators has previously been demonstrated in aged HSCs. Referred to as inflammaging, this type of inflammation has been associated with aging-related immune decline.^8,9  The authors further showed a reduction in exhausted-phenotype CD4+ T cells and CD19+ B cells as well as a reduction in inflammatory markers interleukin (IL)-1α and CXCL5 in the plasma of aged mice after antibody conditioning.

Crucially, the authors validated that the rejuvenation of blood enhanced immunity. Dr. Ross and his colleagues vaccinated the mice and subsequently infected them with the Friend virus to evaluate their immune protection. Aged mice depleted of my-HSCs showed significantly enhanced functional immune responses compared to their untreated counterparts, as evidenced by decreased spleen weight, lower infectious virus levels, and increased virus-specific CD8+ T cells in the spleen.

Lastly, the authors explored the relevance of these findings to humans by examining the expression of my-HSCs markers in human samples, finding that my-HSC marker genes similarly enriched in aged human HSCs.