Chen et al. identify Rad21/cohesin as a critical mediator of inflammation/NF-κB–induced differentiation of hematopoietic stem cells (HSCs). Aging-associated increases in inflammation select for HSCs with disrupted or naturally reduced Rad21/cohesin expression exhibiting increased self-renewal and myeloid-biased differentiation: two hallmark features of the aging hematopoietic system.

Increasing evidence links metabolism, protein synthesis, and growth signaling to impairments in the function of hematopoietic stem and progenitor cells (HSPC) during aging. The Lin28b/Hmga2 pathway controls tissue development and the postnatal downregulation of this pathway limits the self-renewal of adult vs. fetal hematopoietic stem cells (HSC). Igf2bp2 is an RNA binding protein downstream of Lin28b/Hmga2, which regulates mRNA stability and translation. The role of Igf2bp2 in HSC aging is unknown. Here, we show in an analysis of wildtype and Igf2bp2 knockout mice that Igf2bp2 regulates oxidative metabolism in HSPC and the expression of metabolism, protein synthesis, and stemness-related genes in HSC of young mice. Interestingly, Igf2bp2 expression and function strongly decline in HSC aging. In young mice, Igf2bp2-deletion mimics aging-related changes of HSC, including changes in Igf2bp2-target gene expression and the impairment in colony formation and repopulation capacity. In aged mice, Igf2bp2 gene status has no effect on these parameters in HSC. Unexpectedly, Igf2bp2 deficient mice exhibit an amelioration of the aging-associated increase of HSC numbers and myeloid skewed differentiation. Together, Igf2bp2 controls mitochondrial metabolism, protein synthesis, growth, and stemness of young HSC, which is required for full HSC function at young adult age. However, Igf2bp2 gene function is lost during aging and it appears to contribute to HSC aging in two ways: (i) the aging-related loss of Igf2bp2 gene function impairs the growth and repopulation capacity of aging HSC and (ii) the activity of Igf2bp2 at young age contributes to aging-associated HSC expansion and myeloid skewing.

Cationic non-viral vectors show great potential to introduce genetic material into cells, due to their ability to transport large amounts of genetic material and their high synthetic versatility. However, designing materials that are effective without showing toxic effects or undergoing non-specific interactions when applied systemically remains a challenge. The introduction of shielding polymers such as polyethylene glycol (PEG) can enhance biocompatibility and circulation time, however, often impairs transfection efficiency. Herein, a multicomponent polymer system is introduced, based on cationic and hydrophobic particles (P(nBMA46-co-MMA47-co-DMAEMA90), (PBMD)) with high delivery performance and a pH-responsive block copolymer (poly((N-acryloylmorpholine)-b-(2-(carboxy)ethyl acrylamide)) (P(NAM72-b-CEAm74), PNC)) as shielding system, with PNAM as alternative to PEG. The pH-sensitive polymer design promotes biocompatibility and excellent stability at extracellular conditions (pH 7.4) and also allows endosomal escape and thus high transfection efficiency under acidic conditions. PNC shielded particles are below 200 nm in diameter and showed stable pDNA complexation. Further, interaction with human erythrocytes at extracellular conditions (pH 7.4) was prevented, while acidic conditions (pH 6) enabled membrane leakage. The particles demonstrate transfection in adherent (HEK293T) as well as difficult-to-transfect suspension cells (K-562), with comparable or superior efficiency compared to commercial linear poly(ethylenimine) (LPEI). Besides, the toxicity of PNC-shielded particles was significantly minimized, in particular in K-562 cells and erythrocytes. In addition, a pilot in vivo experiment on bone marrow blood cells of mice that were injected with PNC-shielded particles, revealed slightly enhanced cell transfection in comparison to naked pDNA. This study demonstrates the applicability of cationic hydrophobic polymers for transfection of adherent and suspension cells in culture as well as in vivo by co-formulation with pH-responsive shielding polymers, without substantially compromising transfection performance. Graphical Abstract

Planarians are able to stand long periods of starvation by maintaining adult stem cell pools and regenerative capacity. The molecular pathways that are needed for the maintenance of regeneration during starvation are not known. Here, we show that down‐regulation of chaperonin TRiC/CCT subunits abrogates the regeneration capacity of planarians during starvation, but TRiC/CCT subunits are dispensable for regeneration in fed planarians. Under starvation, they are required to maintain mitotic fidelity and for blastema formation. We show that TRiC subunits modulate the unfolded protein response (UPR) and are required to maintain ATP levels in starved planarians. Regenerative defects in starved CCT‐depleted planarians can be rescued by either chemical induction of mild endoplasmic reticulum stress, which leads to induction of the UPR, or by the supplementation of fatty acids. Together, these results indicate that CCT‐dependent UPR induction promotes regeneration of planarians under food restriction.

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