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Cited by 24Mesenchymal stem cell researchLiver physiology and pathologyEndoplasmic Reticulum Stress and Disease

Activation of the EGFR-PI3K-CaM pathway by PRL-1-overexpressing placenta-derived mesenchymal stem cells ameliorates liver cirrhosis via ER stress-dependent calcium

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Kim, Se Ho, Kim, Jae Yeon, Park, Soo Young, Jeong, Won Tae, Kim, Jin Man, Bae, Si Hyun, Kim, Gi Jin·2021·Stem Cell Research & Therapy
DOI 10.1186/s13287-021-02616-yPMC PMC8543968
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Abstract

Background: Cholesterol accumulation and calcium depletion induce hepatic injury via the endoplasmic reticulum (ER) stress response. ER stress regulates the calcium imbalance between the ER and mitochondria. We previously reported that phosphatase of regenerating liver-1 (PRL-1)-overexpressing placenta-derived mesenchymal stem cells (PD-MSCs PRL−1) promoted liver regeneration via mitochondrial dynamics in a cirrhotic rat model. However, the role of PRL-1 in ER stress-dependent calcium is not clear. Therefore, we demonstrated that PD-MSCs PRL−1 improved hepatic functions by regulating ER stress and calcium channels in a rat model of bile duct ligation (BDL). Methods: Liver cirrhosis was induced in Sprague–Dawley (SD) rats using surgically induced BDL for 10 days. PD-MSCs and PD-MSCs PRL−1 (2 × 10 6 cells) were intravenously administered to animals, and their therapeutic effects were analyzed. WB-F344 cells exposed to thapsigargin (TG) were cocultured with PD-MSCs or PD-MSCs PRL−1. Results: ER stress markers, e.g., eukaryotic translation initiation factor 2α (eIF2α), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP), were increased in the nontransplantation group (NTx) compared to the control group. PD-MSCs PRL−1 significantly decreased ER stress markers compared to NTx and induced dynamic changes in calcium channel markers, e.g., sarco/endoplasmic reticulum Ca 2+ -ATPase 2b (SERCA2b), inositol 1,4,5-trisphosphate receptor (IP3R), mitochondrial calcium uniporter (MCU), and voltage-dependent anion channel 1 (VDAC1) (*p < 0.05). Cocultivation of TG-treated WB-F344 cells with PD-MSCs PRL−1 decreased cytosolic calmodulin (CaM) expression and cytosolic and mitochondrial Ca 2+ concentrations. However, the ER Ca 2+ concentration was increased compared to PD-MSCs (*p < 0.05). PRL-1 activated phosphatidylinositol-3-kinase (PI3K) signaling via epidermal growth factor receptor (EGFR), which resulted in calcium increase via CaM expression. Conclusions: These findings suggest that PD-MSCs PRL−1 improved hepatic functions via calcium changes and attenuated ER stress in a BDL-injured rat model. Therefore, these results provide useful data for the development of next-generation MSC-based stem cell therapy for regenerative medicine in chronic liver disease.

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Cited by

Sorted by citations

Authors
Kim, S. H., Kim, J. Y., Park, S. Y., Jeong, W. T., Kim, J. M., Bae, S. H., & Kim, G. J.
Affiliations
  • CHA University (KR)
  • Seoul National University (KR)
  • Catholic University of Korea (KR)
Corresponding author
  • Kim, Jin Man
  • Kim, Gi Jin
ORCID
Venue
Stem Cell Research & Therapy
Publisher
Springer Science and Business Media LLC
Published
2021-10-24
Volume
12
Issue
1
Pages
551-551
ISSN
1757-6512 (ISSN-L)
DOI
10.1186/s13287-021-02616-y
PMC
PMC8543968
OpenAlex
W3210724407
Cited by
24
References
0
Citations by year
2026: 1 · 2025: 6 · 2024: 7 · 2023: 4 · 2022: 6
FWCI
2.39
Type
journal article
Language
en
Open access
Licence
Locations
  • Stem Cell Research & Therapy (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Seoul National University Open Repository (Seoul National University) (submittedVersion)
Funders
  • ministry of education (2020M3A9B302618221)
  • korea health industry development institute (HI17C1050)
Topics
  • Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
Keywords
liver cirrhosis, placenta-derived mesenchymal stem cells, PRL-1, endoplasmic reticulum stress, calcium homeostasis, calmodulin, bile duct ligation, SERCA2b, IP3 receptor, mitochondrial calcium uniporter, VDAC1, mitochondrial calcium, liver regeneration, thapsigargin
MeSH terms
Animals, Calcium, Calmodulin, Female, Liver Cirrhosis, Placenta, Pregnancy, Rats, Inbred F344, Protein Tyrosine Phosphatases, Rats, Sprague-Dawley, Immediate-Early Proteins, Phosphatidylinositol 3-Kinases, Rats, Phosphatidylinositol 3-Kinase, Mesenchymal Stem Cells, Endoplasmic Reticulum Stress, ErbB Receptors

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