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A simple approach f...
A simple approach for restoration of differentiation and function in cryopreserved human hepatocytes
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- Ölander, Magnus (författare)
- Uppsala universitet,Institutionen för farmaci
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- Wiśniewski, Jacek R. (författare)
- Max Planck Inst Biochem, Biochem Prote Grp, Dept Prote & Signal Transduct, D-82152 Martinsried, Germany
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- Flörkemeier, Inken (författare)
- Uppsala universitet,Institutionen för farmaci
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- Handin, Niklas (författare)
- Uppsala universitet,Institutionen för farmaci
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- Urdzik, Jozef (författare)
- Uppsala universitet,Gastrointestinalkirurgi
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- Artursson, Per (författare)
- Uppsala universitet,Institutionen för farmaci,Science for Life Laboratory, SciLifeLab
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(creator_code:org_t)
- 2018-12-17
- 2019
- Engelska.
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Ingår i: Archives of Toxicology. - : Springer Science and Business Media LLC. - 0340-5761 .- 1432-0738. ; 93:3, s. 819-829
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Abstract
Ämnesord
Stäng
- Primary human hepatocytes are used in all facets of liver research, from in vitro studies of xenobiotic disposition and toxicity to the clinical management of liver failure. Unfortunately, cellular stress during isolation and cryopreservation causes a highly unpredictable loss of the ability to attach and form cell-matrix and cell-cell interactions. Reasoning that this problem could be mitigated at the post-thawing stage, we applied label-free quantitative global proteomics to analyze differences between attached and non-attached fractions of cryopreserved human hepatocyte batches. Hepatocytes that were unable to attach to a collagen matrix showed many signs of cellular stress, including a glycolytic phenotype and activation of the heat shock response, ultimately leading to apoptosis activation. Further analysis of the activated stress pathways revealed an increase in early apoptosis immediately post-thawing, which suggested the possibility of stress reversal. Therefore, we transiently treated the cells with compounds aimed at decreasing cellular stress via different mechanisms. Brief exposure to the pan-caspase apoptosis inhibitor Z-VAD-FMK restored attachment ability and promoted a differentiated morphology, as well as formation of 3D spheroids. Further, Z-VAD-FMK treatment restored metabolic and transport functions, with maintained sensitivity to hepatotoxic insults. Altogether, this study shows that differentiation and function of suboptimal human hepatocytes can be restored after cryopreservation, thus markedly increasing the availability of these precious cells.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
Nyckelord
- Apoptosis
- Cellular stress
- Cryopreservation
- Hepatotoxicity
- Human hepatocytes
- Proteomics
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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