Nanchangmycin regulates FYN, PTK2, and MAPK1/3 to control the fibrotic activity of human hepatic stellate cells
Chronic liver injury causes fibrosis, characterized by the formation of scar tissue resulting from excessive accumulation of extracellular matrix (ECM) proteins. Hepatic stellate cell (HSC) myofibroblasts are the primary cell type responsible for liver fibrosis, yet there are currently no therapies...
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2022-05-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/74513 |
| _version_ | 1811203298615623680 |
|---|---|
| author | Wenyang Li Jennifer Y Chen Cheng Sun Robert P Sparks Lorena Pantano Raza-Ur Rahman Sean P Moran Joshua V Pondick Rory Kirchner David Wrobel Michael Bieler Achim Sauer Shannan J Ho Sui Julia F Doerner Jörg F Rippmann Alan C Mullen |
| author_facet | Wenyang Li Jennifer Y Chen Cheng Sun Robert P Sparks Lorena Pantano Raza-Ur Rahman Sean P Moran Joshua V Pondick Rory Kirchner David Wrobel Michael Bieler Achim Sauer Shannan J Ho Sui Julia F Doerner Jörg F Rippmann Alan C Mullen |
| author_sort | Wenyang Li |
| collection | DOAJ |
| description | Chronic liver injury causes fibrosis, characterized by the formation of scar tissue resulting from excessive accumulation of extracellular matrix (ECM) proteins. Hepatic stellate cell (HSC) myofibroblasts are the primary cell type responsible for liver fibrosis, yet there are currently no therapies directed at inhibiting the activity of HSC myofibroblasts. To search for potential anti-fibrotic compounds, we performed a high-throughput compound screen in primary human HSC myofibroblasts and identified 19 small molecules that induce HSC inactivation, including the polyether ionophore nanchangmycin (NCMC). NCMC induces lipid re-accumulation while reducing collagen expression, deposition of collagen in the extracellular matrix, cell proliferation, and migration. We find that NCMC increases cytosolic Ca2+ and reduces the phosphorylated protein levels of FYN, PTK2 (FAK), MAPK1/3 (ERK2/1), HSPB1 (HSP27), and STAT5B. Further, depletion of each of these kinases suppress COL1A1 expression. These studies reveal a signaling network triggered by NCMC to inactivate HSC myofibroblasts and reduce expression of proteins that compose the fibrotic scar. Identification of the antifibrotic effects of NCMC and the elucidation of pathways by which NCMC inhibits fibrosis provide new tools and therapeutic targets that could potentially be utilized to combat the development and progression of liver fibrosis. |
| first_indexed | 2024-04-12T02:53:16Z |
| format | Article |
| id | doaj.art-cf1c49e456d44880b04f03d69fd37ac5 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:53:16Z |
| publishDate | 2022-05-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-cf1c49e456d44880b04f03d69fd37ac52022-12-22T03:50:55ZengeLife Sciences Publications LtdeLife2050-084X2022-05-011110.7554/eLife.74513Nanchangmycin regulates FYN, PTK2, and MAPK1/3 to control the fibrotic activity of human hepatic stellate cellsWenyang Li0https://orcid.org/0000-0002-1110-1099Jennifer Y Chen1Cheng Sun2Robert P Sparks3Lorena Pantano4Raza-Ur Rahman5Sean P Moran6Joshua V Pondick7Rory Kirchner8David Wrobel9Michael Bieler10Achim Sauer11Shannan J Ho Sui12Julia F Doerner13Jörg F Rippmann14Alan C Mullen15https://orcid.org/0000-0002-4096-3106Division of Gastroenterology, Massachusetts General Hospital, Boston, United States; Harvard Medical School, Boston, United StatesDivision of Gastroenterology, Massachusetts General Hospital, Boston, United States; Harvard Medical School, Boston, United StatesDivision of Gastroenterology, Massachusetts General Hospital, Boston, United States; Harvard Medical School, Boston, United StatesDivision of Gastroenterology, Massachusetts General Hospital, Boston, United States; Harvard Medical School, Boston, United StatesHarvard T.H. Chan School of Public Health, Boston, United StatesDivision of Gastroenterology, Massachusetts General Hospital, Boston, United States; Harvard Medical School, Boston, United StatesDivision of Gastroenterology, Massachusetts General Hospital, Boston, United States; Harvard Medical School, Boston, United StatesDivision of Gastroenterology, Massachusetts General Hospital, Boston, United States; Harvard Medical School, Boston, United StatesHarvard T.H. Chan School of Public Health, Boston, United StatesHarvard Medical School, Boston, United StatesBoehringer Ingelheim Pharma GmbH & Co, Biberach, GermanyBoehringer Ingelheim Pharma GmbH & Co, Biberach, GermanyHarvard T.H. Chan School of Public Health, Boston, United StatesBoehringer Ingelheim Pharma GmbH & Co, Biberach, GermanyBoehringer Ingelheim Pharma GmbH & Co, Biberach, GermanyDivision of Gastroenterology, Massachusetts General Hospital, Boston, United States; Harvard Medical School, Boston, United States; Harvard Stem Cell Institute, Cambridge, United StatesChronic liver injury causes fibrosis, characterized by the formation of scar tissue resulting from excessive accumulation of extracellular matrix (ECM) proteins. Hepatic stellate cell (HSC) myofibroblasts are the primary cell type responsible for liver fibrosis, yet there are currently no therapies directed at inhibiting the activity of HSC myofibroblasts. To search for potential anti-fibrotic compounds, we performed a high-throughput compound screen in primary human HSC myofibroblasts and identified 19 small molecules that induce HSC inactivation, including the polyether ionophore nanchangmycin (NCMC). NCMC induces lipid re-accumulation while reducing collagen expression, deposition of collagen in the extracellular matrix, cell proliferation, and migration. We find that NCMC increases cytosolic Ca2+ and reduces the phosphorylated protein levels of FYN, PTK2 (FAK), MAPK1/3 (ERK2/1), HSPB1 (HSP27), and STAT5B. Further, depletion of each of these kinases suppress COL1A1 expression. These studies reveal a signaling network triggered by NCMC to inactivate HSC myofibroblasts and reduce expression of proteins that compose the fibrotic scar. Identification of the antifibrotic effects of NCMC and the elucidation of pathways by which NCMC inhibits fibrosis provide new tools and therapeutic targets that could potentially be utilized to combat the development and progression of liver fibrosis.https://elifesciences.org/articles/74513nanchangmycinliver fibrosishepatic stellate cellscompound screeningFYNcollagen |
| spellingShingle | Wenyang Li Jennifer Y Chen Cheng Sun Robert P Sparks Lorena Pantano Raza-Ur Rahman Sean P Moran Joshua V Pondick Rory Kirchner David Wrobel Michael Bieler Achim Sauer Shannan J Ho Sui Julia F Doerner Jörg F Rippmann Alan C Mullen Nanchangmycin regulates FYN, PTK2, and MAPK1/3 to control the fibrotic activity of human hepatic stellate cells eLife nanchangmycin liver fibrosis hepatic stellate cells compound screening FYN collagen |
| title | Nanchangmycin regulates FYN, PTK2, and MAPK1/3 to control the fibrotic activity of human hepatic stellate cells |
| title_full | Nanchangmycin regulates FYN, PTK2, and MAPK1/3 to control the fibrotic activity of human hepatic stellate cells |
| title_fullStr | Nanchangmycin regulates FYN, PTK2, and MAPK1/3 to control the fibrotic activity of human hepatic stellate cells |
| title_full_unstemmed | Nanchangmycin regulates FYN, PTK2, and MAPK1/3 to control the fibrotic activity of human hepatic stellate cells |
| title_short | Nanchangmycin regulates FYN, PTK2, and MAPK1/3 to control the fibrotic activity of human hepatic stellate cells |
| title_sort | nanchangmycin regulates fyn ptk2 and mapk1 3 to control the fibrotic activity of human hepatic stellate cells |
| topic | nanchangmycin liver fibrosis hepatic stellate cells compound screening FYN collagen |
| url | https://elifesciences.org/articles/74513 |
| work_keys_str_mv | AT wenyangli nanchangmycinregulatesfynptk2andmapk13tocontrolthefibroticactivityofhumanhepaticstellatecells AT jenniferychen nanchangmycinregulatesfynptk2andmapk13tocontrolthefibroticactivityofhumanhepaticstellatecells AT chengsun nanchangmycinregulatesfynptk2andmapk13tocontrolthefibroticactivityofhumanhepaticstellatecells AT robertpsparks nanchangmycinregulatesfynptk2andmapk13tocontrolthefibroticactivityofhumanhepaticstellatecells AT lorenapantano nanchangmycinregulatesfynptk2andmapk13tocontrolthefibroticactivityofhumanhepaticstellatecells AT razaurrahman nanchangmycinregulatesfynptk2andmapk13tocontrolthefibroticactivityofhumanhepaticstellatecells AT seanpmoran nanchangmycinregulatesfynptk2andmapk13tocontrolthefibroticactivityofhumanhepaticstellatecells AT joshuavpondick nanchangmycinregulatesfynptk2andmapk13tocontrolthefibroticactivityofhumanhepaticstellatecells AT rorykirchner nanchangmycinregulatesfynptk2andmapk13tocontrolthefibroticactivityofhumanhepaticstellatecells AT davidwrobel nanchangmycinregulatesfynptk2andmapk13tocontrolthefibroticactivityofhumanhepaticstellatecells AT michaelbieler nanchangmycinregulatesfynptk2andmapk13tocontrolthefibroticactivityofhumanhepaticstellatecells AT achimsauer nanchangmycinregulatesfynptk2andmapk13tocontrolthefibroticactivityofhumanhepaticstellatecells AT shannanjhosui nanchangmycinregulatesfynptk2andmapk13tocontrolthefibroticactivityofhumanhepaticstellatecells AT juliafdoerner nanchangmycinregulatesfynptk2andmapk13tocontrolthefibroticactivityofhumanhepaticstellatecells AT jorgfrippmann nanchangmycinregulatesfynptk2andmapk13tocontrolthefibroticactivityofhumanhepaticstellatecells AT alancmullen nanchangmycinregulatesfynptk2andmapk13tocontrolthefibroticactivityofhumanhepaticstellatecells |