Abstract
Background: The non-healing of diabetic foot ulcers (DFU) is a major cause of high disability, morbidity, and mortality. Thus, new therapeutic targets and methods to help healing in patients with DFUs are major research hotspots.
Objective: This study examined the molecular differences between healing and non-healing DFUs to identify genes associated with DFU healing.
Methods: Differentially expressed genes (DEGs) were identified by bioinformatics. Samples were collected from patients with healing (n=10) and non-healing (n=10) DFUs from September 2021 to September 2022. Interleukin (IL)-34 expression was measured by ELISA and qRT-PCT. The fibroblasts from healing and non-healing DFU were divided according to their gene signatures and subdivided based on their gene expression profile differences.
Results: A comparison of fibroblast subpopulation characteristics revealed that the proportion of subpopulation 4 was significantly higher in non-healing DFUs than in healing DFUs. Subpopulation 4 had 254 upregulated genes and 2402 downregulated genes in the non-healing compared with the healing DFUs. The DEGs were involved in several biological functions, including cytokine activity, receptor-ligand activity, signaling receptor activator activity, and receptor regulator activity. IL-34 was downregulated in non-healing compared with healing DFUs, suggesting a possible role of IL-34 in DFU healing. In the clinical specimens, IL-34 was significantly downregulated in non-healing DFUs, consistent with the bioinformatics results.
Conclusion: IL-34 expression is downregulated in non-healing DFU. IL-34 appears to be involved in DFU healing, but the exact causal relationship remains to be explored.
Graphical Abstract
[http://dx.doi.org/10.21203/rs.3.rs-2390347/v1]
[http://dx.doi.org/10.1016/j.diabres.2021.109119] [PMID: 34879977]
[http://dx.doi.org/10.1111/nyas.13569] [PMID: 29377202]
[http://dx.doi.org/10.1097/j.pbj.0000000000000187] [PMID: 37213252]
[http://dx.doi.org/10.31128/AJGP-11-19-5161] [PMID: 32416652]
[http://dx.doi.org/10.3390/jcm9093009] [PMID: 32961974]
[http://dx.doi.org/10.1186/s13047-020-00383-2] [PMID: 32209136]
[http://dx.doi.org/10.1126/scitranslmed.3009337] [PMID: 25473038]
[http://dx.doi.org/10.1016/j.jphotobiol.2022.112504] [PMID: 35777177]
[http://dx.doi.org/10.1016/j.cmet.2021.07.017] [PMID: 34384520]
[http://dx.doi.org/10.1242/dev.152587] [PMID: 29138288]
[http://dx.doi.org/10.1089/wound.2014.0561] [PMID: 26989578]
[http://dx.doi.org/10.1172/JCI149538] [PMID: 34651581]
[http://dx.doi.org/10.1038/s41586-021-03549-5] [PMID: 33981032]
[http://dx.doi.org/10.1038/s41590-020-0741-2] [PMID: 32747813]
[http://dx.doi.org/10.1016/j.molmed.2020.07.008] [PMID: 32800679]
[http://dx.doi.org/10.1172/JCI93555] [PMID: 29293096]
[http://dx.doi.org/10.3389/fendo.2021.744868] [PMID: 34721299]
[http://dx.doi.org/10.1111/wrr.12437] [PMID: 27102877]
[http://dx.doi.org/10.1038/s41467-021-27801-8] [PMID: 35013299]
[http://dx.doi.org/10.3390/jcm11216335] [PMID: 36362563]
[http://dx.doi.org/10.1126/science.aan6828] [PMID: 28983043]
[http://dx.doi.org/10.1002/ctm2.694] [PMID: 35352511]
[http://dx.doi.org/10.1002/JLB.MR1117-457R] [PMID: 30066957]
[http://dx.doi.org/10.1016/j.cyto.2017.08.020] [PMID: 28886491]
[http://dx.doi.org/10.3390/cancers12010252] [PMID: 31968663]
[PMID: 34497220]
[http://dx.doi.org/10.1186/s41232-020-00129-4] [PMID: 33072227]
[http://dx.doi.org/10.1093/intimm/dxz074] [PMID: 31868884]
[http://dx.doi.org/10.1038/s41598-021-95839-1] [PMID: 34385542]
[http://dx.doi.org/10.1186/ar3693] [PMID: 22264405]
[http://dx.doi.org/10.1016/j.intimp.2018.05.023] [PMID: 29857241]
[http://dx.doi.org/10.1084/jem.20190290] [PMID: 31940023]
[http://dx.doi.org/10.1093/ecco-jcc/jjaa073] [PMID: 32271873]
[http://dx.doi.org/10.1016/j.xjidi.2022.100112] [PMID: 35521044]
[http://dx.doi.org/10.1371/journal.pone.0081665] [PMID: 24339952]
[http://dx.doi.org/10.1530/EC-19-0436] [PMID: 31648183]
[http://dx.doi.org/10.1210/jc.2013-4409] [PMID: 24712570]
[http://dx.doi.org/10.1007/s11033-022-08107-4] [PMID: 36528662]
[http://dx.doi.org/10.1126/scitranslmed.3007096] [PMID: 24920662]
[http://dx.doi.org/10.1017/UPO9781922064004.024]
[http://dx.doi.org/10.3389/fphys.2022.1030851] [PMID: 36505088]
[http://dx.doi.org/10.1098/rsob.200223] [PMID: 32993416]
[http://dx.doi.org/10.3390/medicina57101072] [PMID: 34684109]
[http://dx.doi.org/10.1177/0022034509359125] [PMID: 20139336]
[http://dx.doi.org/10.3390/ijms24010641] [PMID: 36614083]
[http://dx.doi.org/10.1016/j.mtbio.2022.100320] [PMID: 35757026]
[http://dx.doi.org/10.1016/j.dsx.2018.11.060] [PMID: 30641815]
[http://dx.doi.org/10.1016/j.fsi.2020.05.073] [PMID: 32502613]
[http://dx.doi.org/10.1016/j.cyto.2023.156348] [PMID: 37683444]
[http://dx.doi.org/10.1016/bs.apcsb.2019.02.003] [PMID: 31997772]
[http://dx.doi.org/10.1007/s00018-017-2482-4] [PMID: 28258292]
[PMID: 35200127]
[http://dx.doi.org/10.1038/s41598-017-18433-4] [PMID: 29321503]
[http://dx.doi.org/10.1093/humrep/dey037] [PMID: 29579271]
[http://dx.doi.org/10.3389/fimmu.2021.708186] [PMID: 34456917]
[http://dx.doi.org/10.3390/cells11192953] [PMID: 36230913]
[http://dx.doi.org/10.3389/fimmu.2019.02019] [PMID: 31552020]
[http://dx.doi.org/10.7150/thno.50683] [PMID: 33408768]
[http://dx.doi.org/10.1007/s10753-018-0890-8] [PMID: 30194660]
[http://dx.doi.org/10.3390/cells9010070] [PMID: 31892110]
[http://dx.doi.org/10.1016/j.clinbiochem.2019.04.006] [PMID: 30995442]
[PMID: 36564054]
[http://dx.doi.org/10.1159/000454919] [PMID: 27974711]
[http://dx.doi.org/10.1016/j.addr.2018.09.010] [PMID: 30267742]
[http://dx.doi.org/10.1016/j.bioactmat.2022.06.018] [PMID: 35846841]
[http://dx.doi.org/10.1002/ijc.29376] [PMID: 25471534]
[http://dx.doi.org/10.1016/j.intimp.2022.109525] [PMID: 36508917]
[http://dx.doi.org/10.1016/j.cyto.2010.08.005] [PMID: 20829061]