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| Content Provider | Springer Nature : BioMed Central |
|---|---|
| Author | Bayarsaikhan, Delger Bayarsaikhan, Govigerel Lee, Jaesuk Okano, Teruo Kim, Kyungsook Lee, Bonghee |
| Abstract | Background Hemophilia B is an inherited disorder caused by a mutation in the FIX gene, which results in insufficient blood clotting factor IX (FIX) production from hepatocytes. Currently, there are no treatments for hemophilia B patients. The patients should be continuously administrated with clotting factor concentrates 2–3 times a month to prevent bleeding. Therefore, this study aimed to develop an engineered FIX-secreting hepatocyte sheet that can release FIX for an extended period. Within this study, the engineered FIX-secreting hepatocyte sheet was developed by integrating two core technologies, including a gene editing platform to generate FIX-secreting cells and cell sheet technology to improve cell delivery efficacy. Methods The human FIX gene was inserted into the APOC3 site of iPSCs by CRISPR/Cas9, which secretes the target protein after differentiation into hepatocytes. FIX-secreting hepatocyte sheets were obtained by temperature-responsive polymer grafted cell culture dishes (TRCD). Immunohistochemical and functional tests were performed for hepatocyte-like cells differentiated from FIX KI-iPSCs and wild-type iPSCs (WT-iPSCs). After validating the functional activity and secretion of FIX protein, the engineered hepatocyte-like cell sheets were transplanted to NOD/SCID mice for the in vivo experiments. Results The insertion of the human FIX gene into the APOC3 site demonstrated a significant increase in FIX secretion in hepatocyte-like cells differentiated from FIX KI-iPSCs compared with those obtained from WT-iPSCs. Among the iPSCs to hepatocyte differentiation stages, the hepatic endoderm stage was most suitable for seeding the cells on TRCD and generating cell sheets by temperature changes from 37oC to room temperature when the hepatocyte-like cells have reached maturity. The engineered FIX-secreting cell sheets showed intensive expression of the FIX proteins without losing hepatocyte morphology for 20 days. Furthermore, an in vivo study showed that engineered FIX-secreting cell sheets retained their FIX secretion functions for two weeks, whereas single-cell injected traditionally were barely detected in the experimental animals. Conclusions The engineered FIX-secreting cell sheets fabricated from functionally improved iPSCs with practical cell delivery tools could be a promising tool for clinically treating Hemophilia B. |
| Related Links | https://stemcellres.biomedcentral.com/counter/pdf/10.1186/s13287-025-04195-8.pdf |
| Ending Page | 17 |
| Page Count | 17 |
| Starting Page | 1 |
| File Format | HTM / HTML |
| ISSN | 17576512 |
| DOI | 10.1186/s13287-025-04195-8 |
| Journal | Stem Cell Research & Therapy |
| Issue Number | 1 |
| Volume Number | 16 |
| Language | English |
| Publisher | BioMed Central |
| Publisher Date | 2025-02-23 |
| Access Restriction | Open |
| Subject Keyword | Stem Cells Cell Biology Regenerative Medicine Tissue Engineering Biomedical Engineering and Bioengineering CRISPR/Cas9 FIX knock-in Hepatocytes derived from iPSCs APOC3 Cell sheet technology Hepatocyte differentiation Regenerative Medicine/Tissue Engineering |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Medicine Biochemistry, Genetics and Molecular Biology Molecular Medicine |
| Journal Impact Factor | 7.1/2023 |
| 5-Year Journal Impact Factor | 7.9/2023 |
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