Cohesin-mediated NF-{kappa}B signaling limits hematopoietic stem cell self-renewal in aging and inflammation

This study shows that aged hematopoietic stem and progenitor cells (HSPCs) exhibit increased ground-stage NF-B activity, which enhances their responsiveness to undergo differentiation and loss of self-renewal in response to inflammation. The study identifies Rad21/cohesin as a critical mediator of NF-B signaling, which increases chromatin accessibility in the vicinity of NF-B target genes in response to inflammation. Rad21 is required for normal differentiation, but limits self-renewal of hematopoietic stem cells (HSCs) during aging and inflammation in an NF-B–dependent manner. HSCs from aged mice fail to down-regulate Rad21/cohesin and inflammation/differentiation signals in the resolution phase of inflammation. Inhibition of cohesin/NF-B reverts hypersensitivity of aged HSPCs to inflammation-induced differentiation and myeloid-biased HSCs with disrupted/reduced expression of Rad21/cohesin are increasingly selected during aging. Together, Rad21/cohesin-mediated NF-B signaling limits HSPC function during aging and selects for cohesin-deficient HSCs with myeloid-skewed differentiation.

Source: The Journal of Experimental Medicine - January 7, 2019 Category: Internal Medicine Authors: Chen, Z., Amro, E. M., Becker, F., Hölzer, M., Rasa, S. M. M., Njeru, S. N., Han, B., Di Sanzo, S., Chen, Y., Tang, D., Tao, S., Haenold, R., Groth, M., Romanov, V. S., Kirkpatrick, J. M., Kraus, J. M., Kestler, H. A., Marz, M., Ori, A., Neri, F., Tags: Hematopoiesis Articles Source Type: research