Universität zu Köln

Vougioukalaki, Maria, Demmers, Joris, Vermeij, Wilbert P., Baar, Marjolein, Bruens, Serena, Magaraki, Aristea, Kuijk, Ewart ORCID: 0000-0002-1385-6516, Jager, Myrthe ORCID: 0000-0002-1406-1715, Merzouk, Sarra, Brandt, Renata M. C. ORCID: 0000-0003-0514-5623, Kouwenberg, Janneke, van Boxtel, Ruben, Cuppen, Edwin, Pothof, Joris and Hoeijmakers, Jan H. J. (2022). Different responses to DNA damage determine ageing differences between organs. Aging Cell, 21 (4). HOBOKEN: WILEY. ISSN 1474-9726

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Abstract

Organs age differently, causing wide heterogeneity in multimorbidity, but underlying mechanisms are largely elusive. To investigate the basis of organ-specific ageing, we utilized progeroid repair-deficient Ercc1(Delta)(/-) mouse mutants and systematically compared at the tissue, stem cell and organoid level two organs representing ageing extremes. Ercc1(Delta)(/-) intestine shows hardly any accelerated ageing. Nevertheless, we found apoptosis and reduced numbers of intestinal stem cells (ISCs), but cell loss appears compensated by over-proliferation. ISCs retain their organoid-forming capacity, but organoids perform poorly in culture, compared with WT. Conversely, liver ages dramatically, even causing early death in Ercc1-KO mice. Apoptosis, p21, polyploidization and proliferation of various (stem) cells were prominently elevated in Ercc1(Delta)(/-) liver and stem cell populations were either largely unaffected (Sox9+), or expanding (Lgr5+), but were functionally exhausted in organoid formation and development in vitro. Paradoxically, while intestine displays less ageing, repair in WT ISCs appears inferior to liver as shown by enhanced sensitivity to various DNA-damaging agents, and lower lesion removal. Our findings reveal organ-specific anti-ageing strategies. Intestine, with short lifespan limiting time for damage accumulation and repair, favours apoptosis of damaged cells relying on ISC plasticity. Liver with low renewal rates depends more on repair pathways specifically protecting the transcribed compartment of the genome to promote sustained functionality and cell preservation. As shown before, the hematopoietic system with intermediate self-renewal mainly invokes replication-linked mechanisms, apoptosis and senescence. Hence, organs employ different genome maintenance strategies, explaining heterogeneity in organ ageing and the segmental nature of DNA-repair-deficient progerias.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Vougioukalaki, Maria UNSPECIFIED UNSPECIFIED UNSPECIFIED Demmers, Joris UNSPECIFIED UNSPECIFIED UNSPECIFIED Vermeij, Wilbert P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Baar, Marjolein UNSPECIFIED UNSPECIFIED UNSPECIFIED Bruens, Serena UNSPECIFIED UNSPECIFIED UNSPECIFIED Magaraki, Aristea UNSPECIFIED UNSPECIFIED UNSPECIFIED Kuijk, Ewart UNSPECIFIED orcid.org/0000-0002-1385-6516 UNSPECIFIED Jager, Myrthe UNSPECIFIED orcid.org/0000-0002-1406-1715 UNSPECIFIED Merzouk, Sarra UNSPECIFIED UNSPECIFIED UNSPECIFIED Brandt, Renata M. C. UNSPECIFIED orcid.org/0000-0003-0514-5623 UNSPECIFIED Kouwenberg, Janneke UNSPECIFIED UNSPECIFIED UNSPECIFIED van Boxtel, Ruben UNSPECIFIED UNSPECIFIED UNSPECIFIED Cuppen, Edwin UNSPECIFIED UNSPECIFIED UNSPECIFIED Pothof, Joris UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoeijmakers, Jan H. J. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-683952
DOI:	10.1111/acel.13562
Journal or Publication Title:	Aging Cell
Volume:	21
Number:	4
Date:	2022
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1474-9726
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language HEMATOPOIETIC STEM-CELLS; MOUSE MODEL; NUCLEAR ABNORMALITIES; SMALL-INTESTINE; IN-VITRO; REPAIR; LIVER; MECHANISMS; DEFICIENT; ERCC1-XPF Multiple languages Cell Biology; Geriatrics & Gerontology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/68395