PMID- 34689832 OWN - NLM STAT- MEDLINE DCOM- 20211029 LR - 20220531 IS - 1757-6512 (Electronic) IS - 1757-6512 (Linking) VI - 12 IP - 1 DP - 2021 Oct 24 TI - Activation of the EGFR-PI3K-CaM pathway by PRL-1-overexpressing placenta-derived mesenchymal stem cells ameliorates liver cirrhosis via ER stress-dependent calcium. PG - 551 LID - 10.1186/s13287-021-02616-y [doi] LID - 551 AB - 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 x 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 2alpha (eIF2alpha), 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. CI - (c) 2021. The Author(s). FAU - Kim, Se Ho AU - Kim SH AUID- ORCID: 0000-0003-3859-2665 AD - Department of Biomedical Science, CHA University, Seongnam, 13488, Republic of Korea. FAU - Kim, Jae Yeon AU - Kim JY AUID- ORCID: 0000-0002-3457-5190 AD - Department of Biomedical Science, CHA University, Seongnam, 13488, Republic of Korea. AD - Research Institute of Placenta Science, CHA University, Seongnam, 13488, Republic of Korea. FAU - Park, Soo Young AU - Park SY AUID- ORCID: 0000-0002-1469-2787 AD - Department of Biomedical Science, CHA University, Seongnam, 13488, Republic of Korea. FAU - Jeong, Won Tae AU - Jeong WT AUID- ORCID: 0000-0001-8998-2802 AD - Department of Biomedical Science, CHA University, Seongnam, 13488, Republic of Korea. FAU - Kim, Jin Man AU - Kim JM AUID- ORCID: 0000-0002-4751-7125 AD - Department of Oral Microbiology and Immunology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, 08826, Republic of Korea. FAU - Bae, Si Hyun AU - Bae SH AUID- ORCID: 0000-0003-1727-7842 AD - Department of Internal Medicine, Catholic University Medical College, Seoul, 06591, Republic of Korea. FAU - Kim, Gi Jin AU - Kim GJ AUID- ORCID: 0000-0002-2320-7157 AD - Department of Biomedical Science, CHA University, Seongnam, 13488, Republic of Korea. gjkim@cha.ac.kr. AD - Research Institute of Placenta Science, CHA University, Seongnam, 13488, Republic of Korea. gjkim@cha.ac.kr. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20211024 PL - England TA - Stem Cell Res Ther JT - Stem cell research & therapy JID - 101527581 RN - 0 (Calmodulin) RN - 0 (Immediate-Early Proteins) RN - EC 2.7.1.137 (Phosphatidylinositol 3-Kinase) RN - EC 2.7.10.1 (ErbB Receptors) RN - EC 3.1.3.48 (Protein Tyrosine Phosphatases) RN - EC 3.1.3.48 (Ptp4a1 protein, rat) RN - SY7Q814VUP (Calcium) SB - IM MH - Animals MH - Calcium/metabolism MH - Calmodulin MH - *Endoplasmic Reticulum Stress MH - ErbB Receptors MH - Female MH - Immediate-Early Proteins/*genetics MH - *Liver Cirrhosis/therapy MH - *Mesenchymal Stem Cells/metabolism MH - Phosphatidylinositol 3-Kinase MH - Phosphatidylinositol 3-Kinases MH - Placenta/metabolism MH - Pregnancy MH - Protein Tyrosine Phosphatases/*genetics MH - Rats MH - Rats, Inbred F344 MH - Rats, Sprague-Dawley PMC - PMC8543968 OTO - NOTNLM OT - Calcium homeostasis OT - ER stress OT - Liver cirrhosis OT - Liver regeneration OT - Mitochondria OT - Phosphatase of regenerating liver-1 OT - Placenta-derived mesenchymal stem cells COIS- The authors declare that there has no conflict of interest. EDAT- 2021/10/26 06:00 MHDA- 2021/10/30 06:00 PMCR- 2021/10/24 CRDT- 2021/10/25 05:41 PHST- 2021/07/12 00:00 [received] PHST- 2021/10/06 00:00 [accepted] PHST- 2021/10/25 05:41 [entrez] PHST- 2021/10/26 06:00 [pubmed] PHST- 2021/10/30 06:00 [medline] PHST- 2021/10/24 00:00 [pmc-release] AID - 10.1186/s13287-021-02616-y [pii] AID - 2616 [pii] AID - 10.1186/s13287-021-02616-y [doi] PST - epublish SO - Stem Cell Res Ther. 2021 Oct 24;12(1):551. doi: 10.1186/s13287-021-02616-y.