Multimodal omics identifies a lymphoid-biased multipotent progenitor population with limited age-associated remodeling
Year: 2026
Type: article
Abstract: Hematopoietic aging is marked by declining regenerative capacity and a shift from lymphoid to myeloid output. Previous studies have focused primarily on hematopoietic stem cells (HSCs), yet whether aging uniformly remodels the hematopoietic stem and progenitor cell (HSPC) compartment, or selectively affects distinct populations, remains largely unknown. To address this, we profile HSCs and multipotent progenitors MPP1-6 from young and aged mice across transcriptomic, epigenomic, metabolomic and lipidomic layers, together with single-cell division and in vivo serial transplantation assays. We identify young MPP6 (negative for CD150, CD34, CD48 and CD135) as an HSC-like, lymphoid-biased population with long-term reconstitution capacity, positioned within the top-tier of the differentiation hierarchy and marked by low global chromatin accessibility and metabolic activity. Upon aging, MPP6 preserved long-term lymphoid reconstitution, underwent limited transcriptional and regulatory remodeling, and did not accumulate polyunsaturated phospholipids or show mitochondrial oxidation. By contrast, most HSPCs, and particularly HSCs, underwent pronounced age-associated changes, including myeloid-biased expansion, metabolic rewiring, extensive distal regulatory alteration and accumulation of long-chain polyunsaturated phospholipids linked to increased oxidative stress. Pseudotime analysis further resolved the aged MPP6 compartment into two subsets, including a dormant, lymphoid-biased Dlk1-expressing population characterized by reduced mitochondrial activity, which was distinctly affected by inflammatory challenge in vivo. Together, these findings establish MPP6 as a comparatively resilient population within the aged HSPC compartment and suggest that it may represent a potential target for restoring hematopoietic balance.
Source: Blood
Authors: Mari Carmen Romero-Mulero, Julian Wolter-Mess, Mirijam Lia Egg, Anna Konturek-Ciesla, Yu Wei Zhang, Ivan Berest, Jasmin Rettkowski, Helen Demollin, Alessandro Donada, Aishwarya Krishnan, Lucie S.P. Hustin, Karin Jäcklein, Beatriz Silva-Rego, Carolin Wadle, Francesco Cardamone, Isabella Maria Mayer, Dawn Lin, Andreas Trumpp, Nicola Iovino, Grant Challen, Pia Sommerkamp, Leila Perié, Judith B. Zaugg, Katharina Schönberger, Dominic Grün, Timm Schroeder, Maria-Eleni Lalioti, Marta Derecka, Eirini Trompouki, Nina Cabezas-Wallscheid
Institutions: Max Planck Institute of Immunobiology and Epigenetics, ETH Zurich, University of Basel, Inserm, Washington University in St. Louis, Institut Curie, German Cancer Research Center, Centre National de la Recherche Scientifique, Université Paris Sciences et Lettres, Sorbonne Université, Physique des Cellules et Cancers, University of Würzburg, St. Jude Children's Research Hospital, Université Côte d'Azur, Institut de Recherche sur le Cancer et le Vieillissement de Nice
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,500
Awards: G103968205, G181390637, GRK 2344: MeInBio BioInMe: Untersuchung räumlicher und zeitlicher Dynamik der Genregulation mit hochauflösenden Hochdurchsatzverfahren, G259924242, G2899880, AGE-RELATED CHANGES IN HEMATOPOIESIS, G3512865558, G3986724495, G4103076731, EXC 2189: CIBSS Centre for Integrative Biological Signalling Studies, SFB 992: Medizinische Epigenetik (MEDEP) Von grundlegenden Mechanismen zu klinischen Anwendungen, G5224721593, AGE-RELATED CHANGES IN HEMATOPOIESIS, SFB 1425: Die heterozelluläre Natur kardialer Läsionen: Identitäten, Interaktionen, Implikationen
OpenAlex ID: W7225316995