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Theranostics 2022; 12(6):2908-2927. doi:10.7150/thno.69446 This issue Cite

Research Paper

5-Aminolevulinate improves metabolic recovery and cell survival of the liver following cold preservation

Xiaomei Zhang1,2#, Liang Chen1,2#, Wei Liu2,3#, Juan Shen2#, Haobin Sun1,2, Jinliang Liang2, Guo Lv2, Guihua Chen1,2,3, Yang Yang1,2, Jingxing Ou1,2✉

1. Department of Hepatic Surgery and Liver transplantation Center of the Third Affiliated Hospital, Organ Transplantation Institute, Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong province engineering laboratory for transplantation medicine. Guangzhou 510630, China
2. Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China
3. Key Laboratory of Liver disease biotherapy and Translational Medicine of Guangdong Higher Education Institutes, Guangzhou, China.
# These authors contributed equally to this work.

✉ Corresponding author: Jingxing Ou, Tel: 86-20-85252276; Fax: 86-20-85252276; Email: oujx7edu.cn.

Citation:
Zhang X, Chen L, Liu W, Shen J, Sun H, Liang J, Lv G, Chen G, Yang Y, Ou J. 5-Aminolevulinate improves metabolic recovery and cell survival of the liver following cold preservation. Theranostics 2022; 12(6):2908-2927. doi:10.7150/thno.69446. https://www.thno.org/v12p2908.htm
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Abstract

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Rationale: Hibernating thirteen-lined ground squirrels (GS; Ictidomys tridecemlineatus) are naturally adapted to prolonged periods of ultraprofound hypothermia (body temperature < 5 ºC) during torpor, and drastic oscillations of body temperature and ischemia/reperfusion-like stress during their short euthermic interbout arousals. Thus, their superior adaptability may hold tremendous promise for the advancement of donor organ cold preservation and subsequent organ transplantation. However, bridging hibernation research and translational medicine has been impeded by a dearth of in vitro research tools, till the recent establishment of the GS induced pluripotent stem cells (iPSCs). In this study, we reported the generation of functional hepatocyte-like cells (HLCs) from GS iPSCs. As temperature and oxygen supply affect cellular metabolism, we hypothesized that the GS HLCs can metabolically counter drastic temperature and oxygen supply changes. Differentially regulated metabolites can be evaluated and included into the preservation solution to mitigate temperature and ischemia/reperfusion-associated damage to donor livers.

Methods: A protocol has been developed to produce GS iPSCs-derived HLCs. Comparative metabolomic analysis on GS HLCs and human donor liver samples revealed changes in metabolites caused by cold storage and rewarming. Human embryonic stem cell (ESC)-derived HLCs and ex vivo cold preservation and reperfusion of isolated rat livers were used to assess candidate metabolites that may have protective effects against preservation-related injuries.

Results: GS iPSCs were efficiently differentiated into expandable, cryopreservation-compatible and functional HLCs. Metabolomic analysis unveiled distinct changes of mitochondrial metabolites between GS and human cells following cold storage and rewarming. GS and human HLC-based experiments indicated that the metabolism of 5-aminolevulinate (5-ALA) is key to restricting free radical production during rewarming. Survival of human HLCs was significantly increased following cold exposure and rewarming, as supplemented 5-ALA enhanced Complex III activity and improved mitochondrial respiration. Further, 5-ALA mitigated damage in rat livers following 48-h cold preservation and ex vivo reperfusion. Metabolomic and transcriptomic analyses revealed that supplemented 5-ALA promoted both anabolic and catabolic activities while alleviating cell death, inflammation, hypoxia and other stress responses in isolated perfused rat livers.

Conclusion: In the liver, rewarming from ultraprofound hypothermia imposes complex metabolic challenges and stresses on the mitochondria. Metabolites such as 5-ALA can help alleviate mitochondrial stress. Supplementing 5-ALA to the liver preservation solution can substantially improve the functional recovery of rat livers following prolonged cold preservation, rewarming and reperfusion.

Keywords: Hibernator, Organ preservation, Hepatocyte-like cells, Mitochondria, 5-Aminolevulinate

Citation styles

APA
Zhang, X., Chen, L., Liu, W., Shen, J., Sun, H., Liang, J., Lv, G., Chen, G., Yang, Y., Ou, J. (2022). 5-Aminolevulinate improves metabolic recovery and cell survival of the liver following cold preservation. Theranostics, 12(6), 2908-2927. https://doi.org/10.7150/thno.69446.

ACS
Zhang, X.; Chen, L.; Liu, W.; Shen, J.; Sun, H.; Liang, J.; Lv, G.; Chen, G.; Yang, Y.; Ou, J. 5-Aminolevulinate improves metabolic recovery and cell survival of the liver following cold preservation. Theranostics 2022, 12 (6), 2908-2927. DOI: 10.7150/thno.69446.

NLM
Zhang X, Chen L, Liu W, Shen J, Sun H, Liang J, Lv G, Chen G, Yang Y, Ou J. 5-Aminolevulinate improves metabolic recovery and cell survival of the liver following cold preservation. Theranostics 2022; 12(6):2908-2927. doi:10.7150/thno.69446. https://www.thno.org/v12p2908.htm

CSE
Zhang X, Chen L, Liu W, Shen J, Sun H, Liang J, Lv G, Chen G, Yang Y, Ou J. 2022. 5-Aminolevulinate improves metabolic recovery and cell survival of the liver following cold preservation. Theranostics. 12(6):2908-2927.

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