Chhiring Lama, Danielle Isakov, Shira Rosenberg, Miguel Quijada-Álamo, Mirca S Saurty-Seerunghen, Sara Moein, Mathis Nozais, Tsega-Ab Abera, Olivia Sakaguchi, Mansi Totwani, Grace Freed, Leila Zaydon, Chi-Lam Poon, Neelang Parghi, Andrea Kubas-Meyer, Amy X Xie, Mohamed Omar, Daniel Choi, Franco Castillo-Tokumori, Ghaith Abu-Zeinah, Alicia Dillard, Saravanan Ganesan, Nathaniel D Omans, Neville Dusaj, Paulina Chamely, Eleni Mimitou, Peter Smibert, Heidi E Kosiorek, Amylou C Dueck, Rona Weinberg, Ronan Chaligne, Bridget Marcellino, Luigi Marchionni, Sanjay Patel, Paul Simonson, Dan A Landau, Elvin Wagenblast, Ronald Hoffman, Anna S Nam
Compared with traditional specific pathogen-free (SPF) housing, rewilded mice exhibited systemic shifts toward mature immune phenotypes, including increases in effector and memory B and T cells, expansion of antibody-secreting cell subsets, and changes in immunoglobulin isotypes. In the brain, indoor rewilding recalibrated microglial activation of 5xFAD mice, attenuating pro-inflammatory transcriptional programs while enhancing homeostatic, complement, and phagocytic signatures. A strong transcriptional convergence was observed between rewilded and wild mice, with rewilded 5xFAD mice exhibiting greater similarity to human AD transcriptional profiles. Morphological and histochemical analyses confirmed that rewilded microglia adopt metabolically adaptable, homeostatic states that influence amyloid-β plaque binding and clearance.
Inflammation accelerates evolutionary dynamics of hematopoietic stem cells (HSCs) in clonal hematopoiesis and myeloid neoplasms. We studied HSCs, progenitors and immune cells from patients with myeloproliferative neoplasms at baseline and following interferon-α (IFNα) treatment, the only therapy to deplete mutated stem cells. We deployed single-cell multiomics methods that distinguish the IFNα effects on mutated stem cells from the admixed wild-type HSCs, with respect to their differentiation, transcriptomes, immunophenotypes and chromatin accessibility. IFNα simultaneously activated HSCs into two polarized states: a lymphoid progenitor expansion associated with an anti-inflammatory state and an inflammatory myeloid progenitor state derived from HSCs. The augmented lymphoid differentiation balanced the typical myeloproliferative-neoplasm-induced myeloid bias, associated with normalized blood counts. Somatic mutations modified the effects of IFNα on HSC differentiation and cell cycle entry rates. Clonal fitness upon IFNα exposure was due to resistance of CALR- or JAK2-mutated stem cells to differentiate into inflammatory myeloid progenitors.