Intraportally delivered stem cell spheroids localize in the liver and protect hepatocytes against GalN/LPS-induced fulminant hepatic toxicity

Shobha Regmi; Shiva Pathak; Tung Pham Thanh; Tiep Tien Nguyen; Jong Hyuk Sung; Simmyung Yook; Jong Oh Kim; Chul Soon Yong; Inho Choi; Kyoung Oh Doh; Pil Hoon Park; Jun Beom Park; Yoojin Seo; Bieong Kil Kim; Dong Mok Lee; Ik Jae Moon; Hyung Sik Kim; Jee Heon Jeong

doi:10.1186/s13287-019-1337-3

Intraportally delivered stem cell spheroids localize in the liver and protect hepatocytes against GalN/LPS-induced fulminant hepatic toxicity

Shobha Regmi, Shiva Pathak, Tung Pham Thanh, Tiep Tien Nguyen, Jong Hyuk Sung, Simmyung Yook, Jong Oh Kim, Chul Soon Yong, Inho Choi, Kyoung Oh Doh, Pil Hoon Park, Jun Beom Park, Yoojin Seo, Bieong Kil Kim, Dong Mok Lee, Ik Jae Moon, Hyung Sik Kim, Jee Heon Jeong

Department of Pharmacy

Research output: Contribution to journal › Article › peer-review

15 Citations (Scopus)

Abstract

Background: Systemic inflammatory response syndrome (SIRS) is common in severe fulminant hepatic failure (FHF) and has a high mortality rate (20-50%) due to irreversible cerebral edema or sepsis. Stem cell-based treatment has emerged as a promising alternative therapeutic strategy to prolong the survival of patients suffering from FHF via the inhibition of SIRS due to their immunomodulatory effects. Methods: 3D spheroids of adipose-derived mesenchymal stem cells (3D-ADSC) were prepared by the hanging drop method. The efficacy of the 3D-ADSC to rescue FHF was evaluated in a d-galactosamine/lipopolysaccharide (GalN/LPS)-induced mouse model of FHF via intraportal transplantation of the spheroids. Results: Intraportally delivered 3D-ADSC better engrafted and localized into the damaged livers compared to 2D-cultured adipose-derived mesenchymal stem cells (2D-ADSC). Transplantation of 3D-ADSC rescued 50% of mice from FHF-induced lethality, whereas only 20% of mice survived when 2D-ADSC were transplanted. The improved transplantation outcomes correlated with the enhanced immunomodulatory effect of 3D-ADSC in the liver microenvironment. Conclusion: The study shows that the transplantation of optimized 3D-ADSC can efficiently ameliorate GalN/LPS-induced FHF due to improved viability, resistance to exogenous ROS, and enhanced immunomodulatory effects of 3D-ADSC.

Original language	English
Article number	230
Journal	Stem Cell Research and Therapy
Volume	10
Issue number	1
DOIs	https://doi.org/10.1186/s13287-019-1337-3
Publication status	Published - 2019 Oct 16

Bibliographical note

Funding Information:
This study was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Korean Ministry of Science, ICT, and Future Planning (grant no. 2015R1A5A2009124 and 2018R1A5A2023879) and funded by the Ministry of Education (grant no. 2017R1D1A1B03027831); by the Korea Health Technology R & D Project through the Korea Health Industry Development Institute (KHIDI) and the Korean Ministry of Health and Welfare (grant no. HI18C0453); and by the Creative Economy Leading Technology Development Program through the Gyeongsangbuk-Do and Gyeongbuk Science and Technology Promotion Center of Korea (SF316001A).

Publisher Copyright:
© 2019 The Author(s).

All Science Journal Classification (ASJC) codes

Medicine (miscellaneous)
Molecular Medicine
Biochemistry, Genetics and Molecular Biology (miscellaneous)
Cell Biology

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10.1186/s13287-019-1337-3

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Regmi, S., Pathak, S., Thanh, T. P., Nguyen, T. T., Sung, J. H., Yook, S., Kim, J. O., Yong, C. S., Choi, I., Doh, K. O., Park, P. H., Park, J. B., Seo, Y., Kim, B. K., Lee, D. M., Moon, I. J., Kim, H. S., & Jeong, J. H. (2019). Intraportally delivered stem cell spheroids localize in the liver and protect hepatocytes against GalN/LPS-induced fulminant hepatic toxicity. Stem Cell Research and Therapy, 10(1), [230]. https://doi.org/10.1186/s13287-019-1337-3

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title = "Intraportally delivered stem cell spheroids localize in the liver and protect hepatocytes against GalN/LPS-induced fulminant hepatic toxicity",

abstract = "Background: Systemic inflammatory response syndrome (SIRS) is common in severe fulminant hepatic failure (FHF) and has a high mortality rate (20-50%) due to irreversible cerebral edema or sepsis. Stem cell-based treatment has emerged as a promising alternative therapeutic strategy to prolong the survival of patients suffering from FHF via the inhibition of SIRS due to their immunomodulatory effects. Methods: 3D spheroids of adipose-derived mesenchymal stem cells (3D-ADSC) were prepared by the hanging drop method. The efficacy of the 3D-ADSC to rescue FHF was evaluated in a d-galactosamine/lipopolysaccharide (GalN/LPS)-induced mouse model of FHF via intraportal transplantation of the spheroids. Results: Intraportally delivered 3D-ADSC better engrafted and localized into the damaged livers compared to 2D-cultured adipose-derived mesenchymal stem cells (2D-ADSC). Transplantation of 3D-ADSC rescued 50% of mice from FHF-induced lethality, whereas only 20% of mice survived when 2D-ADSC were transplanted. The improved transplantation outcomes correlated with the enhanced immunomodulatory effect of 3D-ADSC in the liver microenvironment. Conclusion: The study shows that the transplantation of optimized 3D-ADSC can efficiently ameliorate GalN/LPS-induced FHF due to improved viability, resistance to exogenous ROS, and enhanced immunomodulatory effects of 3D-ADSC.",

author = "Shobha Regmi and Shiva Pathak and Thanh, {Tung Pham} and Nguyen, {Tiep Tien} and Sung, {Jong Hyuk} and Simmyung Yook and Kim, {Jong Oh} and Yong, {Chul Soon} and Inho Choi and Doh, {Kyoung Oh} and Park, {Pil Hoon} and Park, {Jun Beom} and Yoojin Seo and Kim, {Bieong Kil} and Lee, {Dong Mok} and Moon, {Ik Jae} and Kim, {Hyung Sik} and Jeong, {Jee Heon}",

note = "Funding Information: This study was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Korean Ministry of Science, ICT, and Future Planning (grant no. 2015R1A5A2009124 and 2018R1A5A2023879) and funded by the Ministry of Education (grant no. 2017R1D1A1B03027831); by the Korea Health Technology R & D Project through the Korea Health Industry Development Institute (KHIDI) and the Korean Ministry of Health and Welfare (grant no. HI18C0453); and by the Creative Economy Leading Technology Development Program through the Gyeongsangbuk-Do and Gyeongbuk Science and Technology Promotion Center of Korea (SF316001A). Publisher Copyright: {\textcopyright} 2019 The Author(s).",

year = "2019",

month = oct,

day = "16",

doi = "10.1186/s13287-019-1337-3",

language = "English",

volume = "10",

journal = "Stem Cell Research and Therapy",

issn = "1757-6512",

publisher = "BioMed Central",

number = "1",

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Regmi, S, Pathak, S, Thanh, TP, Nguyen, TT, Sung, JH, Yook, S, Kim, JO, Yong, CS, Choi, I, Doh, KO, Park, PH, Park, JB, Seo, Y, Kim, BK, Lee, DM, Moon, IJ, Kim, HS & Jeong, JH 2019, 'Intraportally delivered stem cell spheroids localize in the liver and protect hepatocytes against GalN/LPS-induced fulminant hepatic toxicity', Stem Cell Research and Therapy, vol. 10, no. 1, 230. https://doi.org/10.1186/s13287-019-1337-3

TY - JOUR

T1 - Intraportally delivered stem cell spheroids localize in the liver and protect hepatocytes against GalN/LPS-induced fulminant hepatic toxicity

AU - Regmi, Shobha

AU - Pathak, Shiva

AU - Thanh, Tung Pham

AU - Nguyen, Tiep Tien

AU - Sung, Jong Hyuk

AU - Yook, Simmyung

AU - Kim, Jong Oh

AU - Yong, Chul Soon

AU - Choi, Inho

AU - Doh, Kyoung Oh

AU - Park, Pil Hoon

AU - Park, Jun Beom

AU - Seo, Yoojin

AU - Kim, Bieong Kil

AU - Lee, Dong Mok

AU - Moon, Ik Jae

AU - Kim, Hyung Sik

AU - Jeong, Jee Heon

N1 - Funding Information: This study was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Korean Ministry of Science, ICT, and Future Planning (grant no. 2015R1A5A2009124 and 2018R1A5A2023879) and funded by the Ministry of Education (grant no. 2017R1D1A1B03027831); by the Korea Health Technology R & D Project through the Korea Health Industry Development Institute (KHIDI) and the Korean Ministry of Health and Welfare (grant no. HI18C0453); and by the Creative Economy Leading Technology Development Program through the Gyeongsangbuk-Do and Gyeongbuk Science and Technology Promotion Center of Korea (SF316001A). Publisher Copyright: © 2019 The Author(s).

PY - 2019/10/16

Y1 - 2019/10/16

N2 - Background: Systemic inflammatory response syndrome (SIRS) is common in severe fulminant hepatic failure (FHF) and has a high mortality rate (20-50%) due to irreversible cerebral edema or sepsis. Stem cell-based treatment has emerged as a promising alternative therapeutic strategy to prolong the survival of patients suffering from FHF via the inhibition of SIRS due to their immunomodulatory effects. Methods: 3D spheroids of adipose-derived mesenchymal stem cells (3D-ADSC) were prepared by the hanging drop method. The efficacy of the 3D-ADSC to rescue FHF was evaluated in a d-galactosamine/lipopolysaccharide (GalN/LPS)-induced mouse model of FHF via intraportal transplantation of the spheroids. Results: Intraportally delivered 3D-ADSC better engrafted and localized into the damaged livers compared to 2D-cultured adipose-derived mesenchymal stem cells (2D-ADSC). Transplantation of 3D-ADSC rescued 50% of mice from FHF-induced lethality, whereas only 20% of mice survived when 2D-ADSC were transplanted. The improved transplantation outcomes correlated with the enhanced immunomodulatory effect of 3D-ADSC in the liver microenvironment. Conclusion: The study shows that the transplantation of optimized 3D-ADSC can efficiently ameliorate GalN/LPS-induced FHF due to improved viability, resistance to exogenous ROS, and enhanced immunomodulatory effects of 3D-ADSC.

AB - Background: Systemic inflammatory response syndrome (SIRS) is common in severe fulminant hepatic failure (FHF) and has a high mortality rate (20-50%) due to irreversible cerebral edema or sepsis. Stem cell-based treatment has emerged as a promising alternative therapeutic strategy to prolong the survival of patients suffering from FHF via the inhibition of SIRS due to their immunomodulatory effects. Methods: 3D spheroids of adipose-derived mesenchymal stem cells (3D-ADSC) were prepared by the hanging drop method. The efficacy of the 3D-ADSC to rescue FHF was evaluated in a d-galactosamine/lipopolysaccharide (GalN/LPS)-induced mouse model of FHF via intraportal transplantation of the spheroids. Results: Intraportally delivered 3D-ADSC better engrafted and localized into the damaged livers compared to 2D-cultured adipose-derived mesenchymal stem cells (2D-ADSC). Transplantation of 3D-ADSC rescued 50% of mice from FHF-induced lethality, whereas only 20% of mice survived when 2D-ADSC were transplanted. The improved transplantation outcomes correlated with the enhanced immunomodulatory effect of 3D-ADSC in the liver microenvironment. Conclusion: The study shows that the transplantation of optimized 3D-ADSC can efficiently ameliorate GalN/LPS-induced FHF due to improved viability, resistance to exogenous ROS, and enhanced immunomodulatory effects of 3D-ADSC.

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U2 - 10.1186/s13287-019-1337-3

DO - 10.1186/s13287-019-1337-3

M3 - Article

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AN - SCOPUS:85073430163

SN - 1757-6512

VL - 10

JO - Stem Cell Research and Therapy

JF - Stem Cell Research and Therapy

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M1 - 230

ER -

Intraportally delivered stem cell spheroids localize in the liver and protect hepatocytes against GalN/LPS-induced fulminant hepatic toxicity

Abstract

Bibliographical note

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