{"doi":"10.3390/cells12020214","title":"Notch Blockade Specifically in Bone Marrow-Derived FSP-1-Positive Cells Ameliorates Renal Fibrosis","abstract":"<jats:p>Background: The infiltration of inflammatory cells during a kidney injury stimulates myofibroblast activation leading to kidney fibrosis. Fibroblast-specific protein 1 (FSP-1) positive cells have been reported as either myofibroblasts or monocytes during tissue fibrosis. The functions of FSP-1+ cells that are associated with the development of renal fibrosis and the signaling pathways that regulate FSP-1+ cell activation have not been well defined. Methods: In mice with unilateral ureteral obstruction (UUO), we characterized FSP-1+ cells and determined the role of the Notch signaling pathway in the activation of bone marrow-derived FSP-1+ cells during kidney fibrosis. Results: In kidneys from mice with UUO, the FSP-1+ cells accumulated significantly in the tubulointerstitial area. By using immunostaining and FSP-1 reporter mice, we found that FSP-1 was co-stained with inflammatory cell markers, but not myofibroblast markers. Results from mice with bone marrow transplantations showed that FSP-1+ cells in obstructed kidneys represent a bone marrow-derived population of inflammatory cells. In cultured FSP-1+ cells, the inhibition of Notch signaling suppressed the activation and cytokine secretion of FSP-1+ cells that were induced by LPS but not by IL-4. The specific KO or blockade of Notch signaling in bone marrow-derived FSP-1+ cells suppressed UUO-induced ECM deposition, the infiltration of FSP-1+ inflammatory cells, and cytokine production. These responses ameliorated myofibroblast accumulation and renal fibrosis in obstructed kidneys. Conclusion: Our study reveals that most FSP-1+ cells in obstructed kidneys are activated macrophages that are derived from bone marrow and that Notch signaling activates the production of M1 cytokines in FSP-1+ monocytes/macrophages, which is important for renal inflammation and fibrosis.</jats:p>","journal":"Cells","year":2023,"id":690008,"datarank":0.29188652235829704,"base_score":1.9459101490553132,"endowment":1.9459101490553132,"self_citation_contribution":0.29188652235829704,"citation_network_contribution":0.0,"self_endowment_contribution":0.29188652235829704,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1802620,"name":"Ming Liang","orcid":null,"position":1,"is_corresponding":false},{"id":370162,"name":"Fengzhang Huang","orcid":null,"position":2,"is_corresponding":false},{"id":1802621,"name":"Owen H. Cheng","orcid":null,"position":3,"is_corresponding":false},{"id":370163,"name":"Xiaoguang Xiao","orcid":null,"position":4,"is_corresponding":false},{"id":1802622,"name":"Tae Hoon Lee","orcid":null,"position":5,"is_corresponding":false},{"id":1562327,"name":"Luan Truong","orcid":null,"position":6,"is_corresponding":false},{"id":368661,"name":"Jizhong Cheng","orcid":"0000-0002-2779-2904","position":7,"is_corresponding":false},{"id":1802619,"name":"Yongdong Wu","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Notch Blockade Specifically in Bone Marrow-Derived FSP-1-Positive Cells Ameliorates Renal Fibrosis","abstract":"<jats:p>Background: The infiltration of inflammatory cells during a kidney injury stimulates myofibroblast activation leading to kidney fibrosis. Fibroblast-specific protein 1 (FSP-1) positive cells have been reported as either myofibroblasts or monocytes during tissue fibrosis. The functions of FSP-1+ cells that are associated with the development of renal fibrosis and the signaling pathways that regulate FSP-1+ cell activation have not been well defined. Methods: In mice with unilateral ureteral obstruction (UUO), we characterized FSP-1+ cells and determined the role of the Notch signaling pathway in the activation of bone marrow-derived FSP-1+ cells during kidney fibrosis. Results: In kidneys from mice with UUO, the FSP-1+ cells accumulated significantly in the tubulointerstitial area. By using immunostaining and FSP-1 reporter mice, we found that FSP-1 was co-stained with inflammatory cell markers, but not myofibroblast markers. Results from mice with bone marrow transplantations showed that FSP-1+ cells in obstructed kidneys represent a bone marrow-derived population of inflammatory cells. In cultured FSP-1+ cells, the inhibition of Notch signaling suppressed the activation and cytokine secretion of FSP-1+ cells that were induced by LPS but not by IL-4. The specific KO or blockade of Notch signaling in bone marrow-derived FSP-1+ cells suppressed UUO-induced ECM deposition, the infiltration of FSP-1+ inflammatory cells, and cytokine production. These responses ameliorated myofibroblast accumulation and renal fibrosis in obstructed kidneys. Conclusion: Our study reveals that most FSP-1+ cells in obstructed kidneys are activated macrophages that are derived from bone marrow and that Notch signaling activates the production of M1 cytokines in FSP-1+ monocytes/macrophages, which is important for renal inflammation and fibrosis.</jats:p>","is_dataset_classified":null,"base_score":1.9459101490553132,"endowment":1.9459101490553132,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"36672147","pmcid":"PMC9856686","openalex_id":"https://openalex.org/W4313493834","authors":[],"funders":[{"funder_name":"NIH","grant_id":"R01-DK095867","title":null},{"funder_name":"NIH","grant_id":"R01-DK0124259","title":null},{"funder_name":"NIH","grant_id":"15GRNT25700209","title":null},{"funder_name":"NIH","grant_id":"NSFC 82170761","title":null},{"funder_name":"NIDDK NIH HHS","grant_id":"R01 DK095867","title":null},{"funder_name":"NIDDK NIH HHS","grant_id":"R01 DK124259","title":null},{"funder_name":"National Institutes of Health","grant_id":"1R01DK095867-01A1","title":"CHRONIC KIDNEY DISEASE ADVERSELY INFLUENCES VASCULAR FUNCTIONS"},{"funder_name":"National Institutes of Health","grant_id":"5R01DK124259-04","title":"Interplay between skeletal muscle catabolism and remodeling of arteriovenous fistulae via YAP1/TAZ signaling"}],"total_grants":8,"fwci":1.5071,"citation_percentile":0.80735438,"influential_citations":0,"citation_trend":[{"year":2023,"count":2},{"year":2024,"count":3},{"year":2025,"count":1}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://www.mdpi.com/2073-4409/12/2/214/pdf?version=1672831219","host_type":"journal"},{"url":"https://www.mdpi.com/2073-4409/12/2/214/pdf?version=1672831219","host_type":"GOLD"},{"url":"https://www.mdpi.com/2073-4409/12/2/214/pdf?version=1672831219","host_type":"publisher"},{"url":"https://www.mdpi.com/2073-4409/12/2/214/pdf","host_type":"publisher"},{"url":"https://doi.org/10.3390/cells12020214","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/36672147","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/9856686","host_type":"repository"},{"url":"https://digitalcommons.library.tmc.edu/baylor_docs/1730","host_type":"repository"},{"url":"https://doaj.org/article/2b68a24576cf4a61be17afd7c4ded1b6","host_type":"repository"},{"url":"https://dx.doi.org/10.3390/cells12020214","host_type":"repository"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC9856686/pdf/cells-12-00214.pdf","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC9856686","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC9856686?pdf=render","host_type":"Europe_PMC"},{"url":"http://dx.doi.org/10.3390/cells12020214","host_type":""},{"url":"https://doi.org/https://doi.org/10.3390/cells12020214","host_type":""}],"fields_of_study":["Tissue Engineering and Regenerative Medicine","Abdominal vascular conditions and treatments","Neonatal Respiratory Health Research","Medicine","Biology","0301 basic medicine","03 medical and health sciences","0303 health sciences","Animals","Mice","Bone Marrow","Cytokines","Fibrosis","Kidney","Kidney Diseases","S100 Calcium-Binding Protein A4","Ureteral Obstruction"],"mesh_terms":["S100 Calcium-Binding Protein A4","Animals","Bone Marrow","Fibrosis","Kidney","Kidney Diseases","Ureteral Obstruction","Cytokines","Mice"],"keywords":["Myofibroblast","Bone marrow","Fibrosis","Medicine","Kidney","Pathology","Cytokine","Endocrinology","Internal medicine","Macrophage","Notch Signaling Pathway","Unilateral Ureter Obstruction (Uuo)","Fibroblast Specific Protein-1 (Fsp-1)","Medical Sciences","610","Diseases","Article","Mice","Medical Specialties","Medicine and Health Sciences","Animals","S100 Calcium-Binding Protein A4","QH573-671","Nephrology","Cytokines","Kidney Diseases","Cytology","Ureteral Obstruction"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-22T20:39:20.237819Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}