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Mitochondrial dysfunction and low-grade inflammation have been implicated in different pain conditions, but whether fibroblast mitochondrial health and cytokine secretion contribute to painful DPN is unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We conducted an integrated cellular and molecular profiling of dermal fibroblasts and skin biopsies from 30 participants, grouped into control participants (\n                      <jats:italic>n<\/jats:italic>\n                      =5), diabetes without DPN (\n                      <jats:italic>n<\/jats:italic>\n                      =7), pain-free DPN (\n                      <jats:italic>n<\/jats:italic>\n                      =7) and painful DPN (\n                      <jats:italic>n<\/jats:italic>\n                      =11). Fibroblast cultures (\n                      <jats:italic>n<\/jats:italic>\n                      =24) were evaluated for morphology, growth rate, phenotype, inflammatory mediator secretion and mitochondrial function. Immunohistochemistry of skin biopsies was used to assess fibroblast density, mitochondrial markers and immune cell infiltration.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Fibroblast morphology and proliferation did not differ significantly between groups. Flow cytometric profiling revealed no significant differences in fibroblast subtype distributions across groups. Inflammatory mediator secretion was limited. Mitochondrial mass, membrane potential, reactive oxygen species production and bioenergetic parameters were not different across groups. Skin biopsy analyses confirmed comparable fibroblast density and mitochondrial profiles across groups, regardless of neuropathy or pain. Notably, dermal macrophage infiltration was significantly elevated in the painful DPN group (mean ~8%; ANOVA\n                      <jats:italic>p<\/jats:italic>\n                      =0.02; painful DPN vs control participants\n                      <jats:italic>p<\/jats:italic>\n                      =0.02; painful DPN vs pain-free DPN\n                      <jats:italic>p<\/jats:italic>\n                      =0.07), consistent with prior findings from the same cohort, while Langerhans cell area fraction did not differ between groups.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>Fibroblasts from participants with painful DPN did not differ in inflammatory and mitochondrial profiles compared with those from pain-free DPN. However, persistent dermal macrophage infiltration in painful DPN suggests a stable immune-activated microenvironment, potentially contributing to pain maintenance. Our results suggest that immune-related, rather than fibroblast-intrinsic, mechanisms could play a role in sustaining neuropathic pain in painful DPN.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-025-06660-8","type":"journal-article","created":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T17:26:04Z","timestamp":1769448364000},"page":"1354-1369","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Dermal fibroblast mitochondrial profiles in painful diabetic neuropathy"],"prefix":"10.1007","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-7677-4210","authenticated-orcid":false,"given":"Julie Mie M\u00f8lgaard","family":"Bentzen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8323-1394","authenticated-orcid":false,"given":"Peter Kolind","family":"Brask-Thomsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9893-237X","authenticated-orcid":false,"given":"Maiken","family":"Krogsb\u00e6k","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9770-6517","authenticated-orcid":false,"given":"Xiaoli","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8084-4646","authenticated-orcid":false,"given":"Jens Randel","family":"Nyengaard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0411-4403","authenticated-orcid":false,"given":"Sandra Sif","family":"Gylfadottir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7082-9576","authenticated-orcid":false,"given":"Pall","family":"Karlsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5541-0240","authenticated-orcid":false,"given":"Nanna Brix","family":"Finnerup","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3470-5589","authenticated-orcid":false,"given":"Rikke Katrine Jentoft","family":"Olsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8088-1666","authenticated-orcid":false,"given":"Zahra","family":"Nochi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,26]]},"reference":[{"key":"6660_CR1","doi-asserted-by":"publisher","first-page":"2204","DOI":"10.1016\/j.pain.2011.06.017","volume":"152","author":"TS Jensen","year":"2011","unstructured":"Jensen TS, Baron R, Haanpaa M et al (2011) A new definition of neuropathic pain. 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This study is supported by the Lundbeck Foundation (Grant R359-2020-2620, NBF), Aarhus County Research Initiative (RKJO) and the Novo Nordisk Foundation (NNF18OC0052301, PK). This work is part of the International Diabetic Neuropathy Consortium (IDNC) research program, which was supported by the Novo Nordisk Foundation (NNF14SA0006).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"PK has, over the past 3 years, received honoraria from Vertex Pharmaceuticals, Astra Zeneca and WinSanTor, outside the scope of this work. NBF has received consultancy fees from NeuroPN, Saniona, PharmNovo and Tris Pharma, and has undertaken consultancy work for Aarhus University with remunerated work for AKIGAI and Merz, all outside the submitted work. The authors declare that there are no other relationships or activities that might bias, or be perceived to bias, their work.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 relationships and activities"}},{"value":"All authors meet the ICMJE uniform requirements for authorship and approved the final version of the manuscript. ZN, RKJO and NBF conceived the study and contributed to its design. JMMB planned and performed the cellular and mitochondrial experiments, including flow cytometry, and conducted data analysis. PKB-T and SSG contributed to clinical data acquisition and skin biopsy collection. PK, XH and MK performed in situ experiments, including intraepidermal nerve fibre density, Langerhans cell and macrophage quantification, and fibroblast\/mitochondrial staining. JRN acquired and processed fibroblast cell size data. All authors contributed to data interpretation and critical revision of the manuscript for important intellectual content. ZN drafted the manuscript and is responsible for the integrity of the work as a whole.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}