{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T17:44:51Z","timestamp":1789062291869,"version":"build-2803163510"},"reference-count":42,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2024,11,4]],"date-time":"2024-11-04T00:00:00Z","timestamp":1730678400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Japan Society for the Promotion of Science","award":["19K08525"],"award-info":[{"award-number":["19K08525"]}]},{"name":"Japan Society for the Promotion of Science","award":["22K08224"],"award-info":[{"award-number":["22K08224"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>A comprehensive understanding of the cardio-spleen-bone marrow immune cell axis is essential for elucidating the alterations occurring during the pathogenesis of diabetes mellitus (DM). This study investigates the dynamics of immune cell kinetics in DM after myocardial infarction (MI) over time. MI was induced in diabetic and healthy control groups using C57BL\/N6 mice, with sacrifices occurring at days 1, 3, 7, and 28 post-MI to collect heart, peripheral blood (PB), spleen, and bone marrow (BM) samples. Cell suspensions from each organ were isolated and analyzed via flow cytometry. Additionally, the endothelial progenitor cell-colony-forming assay (EPC-CFA) was performed using mononuclear cells derived from BM, PB, and the spleen. The results indicated that, despite normal production in BM and the spleen, CD45+ cells were lower in the PB of DM mice at days 1 to 3. Further analysis revealed a reduction in total and pro-inflammatory neutrophils (N1s) in PB at days 1 to 3 and in the spleen at days 3 to 7 in DM mice, suggesting that DM-induced alterations in splenic neutrophils fail to meet the demand in PB and ischemic tissues. Infiltrating macrophages (total, M1, M2) were reduced at day 3 in the DM-ischemic heart, with total and M1 (days 1\u20133) and M2 (days 3\u20137) macrophages being significantly decreased in DM-PB compared to controls, indicating impaired macrophage recruitment and polarization in DM. Myeloid dendritic cells (mDCs) in the heart were higher from days 1 to 7, which corresponded with the enhanced recruitment of CD8+ cells from days 1 to 28 in the DM-infarcted myocardium. Total CD4+ cells decreased in DM-PB at days 1 to 3, suggesting a delayed adaptive immune response to MI. B cells were reduced in PB at days 1 to 3, in myocardium at day 3, and in the spleen at day 7, indicating compromised mobilization from BM. EPC-CFA results showed a marked decrease in definitive EPC colonies in the spleen and BM from days 1 to 28 in DM mice compared to controls in vitro, highlighting that DM severely impairs EPC colony-forming activity by limiting the differentiation of EPCs from primitive to definitive forms. Taking together, this study underscores significant disruptions in the cardio-spleen-bone marrow immune cell axis following MI in DM, revealing delayed innate and adaptive immune responses along with impaired EPC differentiation.<\/jats:p>","DOI":"10.3390\/ijms252111833","type":"journal-article","created":{"date-parts":[[2024,11,4]],"date-time":"2024-11-04T05:41:23Z","timestamp":1730698883000},"page":"11833","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Cardioimmunology in Health and Diseases: Impairment of the Cardio-Spleno-Bone Marrow Axis Following Myocardial Infarction in Diabetes Mellitus"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5490-9365","authenticated-orcid":false,"given":"Amankeldi A.","family":"Salybekov","sequence":"first","affiliation":[{"name":"Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura 247-8533, Japan"},{"name":"Shonan Research Institute of Innovative Medicine, Shonan Kamakura General Hospital, Kamakura 247-8533, Japan"},{"name":"Department of Advanced Medicine Science, Tokai University School of Medicine, Isehara 259-1193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanat","family":"Tashov","sequence":"additional","affiliation":[{"name":"Department of Advanced Medicine Science, Tokai University School of Medicine, Isehara 259-1193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yin","family":"Sheng","sequence":"additional","affiliation":[{"name":"Department of Advanced Medicine Science, Tokai University School of Medicine, Isehara 259-1193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ainur","family":"Salybekova","sequence":"additional","affiliation":[{"name":"Department of Advanced Medicine Science, Tokai University School of Medicine, Isehara 259-1193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiko","family":"Shinozaki","sequence":"additional","affiliation":[{"name":"Teaching and Research Support Core Center, Tokai University School of Medicine, Isehara 259-1193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takayuki","family":"Asahara","sequence":"additional","affiliation":[{"name":"Shonan Research Institute of Innovative Medicine, Shonan Kamakura General Hospital, Kamakura 247-8533, Japan"},{"name":"Department of Advanced Medicine Science, Tokai University School of Medicine, Isehara 259-1193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuzo","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura 247-8533, Japan"},{"name":"Shonan Research Institute of Innovative Medicine, Shonan Kamakura General Hospital, Kamakura 247-8533, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Pluijmert, N.J., Atsma, D.E., and Quax, P.H. (2021). Post-ischemic myocardial inflammatory response: A complex and dynamic process susceptible to immunomodulatory therapies. Front. Cardiovasc. Med., 8.","DOI":"10.3389\/fcvm.2021.647785"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1161\/CIRCRESAHA.110.226936","article-title":"The emerging role of innate immunity in the heart and vascular system: For whom the cell tolls","volume":"108","author":"Mann","year":"2011","journal-title":"Circ. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1038\/s41569-019-0315-x","article-title":"Reappraising the role of inflammation in heart failure","volume":"17","author":"Adamo","year":"2020","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1126\/science.1175202","article-title":"Identification of splenic reservoir monocytes and their deployment to inflammatory sites","volume":"325","author":"Swirski","year":"2009","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.jcmg.2014.10.009","article-title":"Splenic metabolic activity predicts risk of future cardiovascular events: Demonstration of a cardiosplenic axis in humans","volume":"8","author":"Emami","year":"2015","journal-title":"JACC. Cardiovasc. Imaging"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1038\/nri3399","article-title":"Neutrophil recruitment and function in health and inflammation","volume":"13","author":"Kolaczkowska","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1126\/science.1183021","article-title":"Regulation of adaptive immunity by the innate immune system","volume":"327","author":"Iwasaki","year":"2010","journal-title":"Science"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1038\/nri3073","article-title":"Protective and pathogenic functions of macrophage subsets","volume":"11","author":"Murray","year":"2011","journal-title":"Nat. Rev. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1016\/j.it.2011.04.009","article-title":"Neutrophil clearance: When the party is over, clean-up begins","volume":"32","author":"Bratton","year":"2011","journal-title":"Trends Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1755-1536-6-11","article-title":"Neutrophil roles in left ventricular remodeling following myocardial infarction","volume":"6","author":"Ma","year":"2013","journal-title":"Fibrogenesis Tissue Repair"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1093\/cvr\/cvw024","article-title":"Temporal neutrophil polarization following myocardial infarction","volume":"110","author":"Ma","year":"2016","journal-title":"Cardiovasc. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1161\/CIRCRESAHA.111.243162","article-title":"Regulation of the inflammatory response in cardiac repair","volume":"110","author":"Frangogiannis","year":"2012","journal-title":"Circ. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3037","DOI":"10.1084\/jem.20070885","article-title":"The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions","volume":"204","author":"Nahrendorf","year":"2007","journal-title":"J. Exp. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3485","DOI":"10.1111\/j.1582-4934.2009.00707.x","article-title":"Classically and alternatively activated macrophages contribute to tissue remodelling after myocardial infarction","volume":"13","author":"Troidl","year":"2009","journal-title":"J. Cell. Mol. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1856","DOI":"10.1007\/s00125-013-2918-9","article-title":"An unbalanced monocyte polarisation in peripheral blood and bone marrow of patients with type 2 diabetes has an impact on microangiopathy","volume":"56","author":"Fadini","year":"2013","journal-title":"Diabetologia"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1126\/science.1230719","article-title":"Leukocyte behavior in atherosclerosis, myocardial infarction, and heart failure","volume":"339","author":"Swirski","year":"2013","journal-title":"Science"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.imlet.2016.06.001","article-title":"Human monocytes and macrophages undergo M1-type inflammatory polarization in response to high levels of glucose","volume":"176","author":"Terrazas","year":"2016","journal-title":"Immunol. Lett."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1016\/j.cmet.2013.04.001","article-title":"Hyperglycemia Promotes Myelopoiesis and Impairs the Resolution of Atherosclerosis","volume":"17","author":"Nagareddy","year":"2013","journal-title":"Cell Metab."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"13344","DOI":"10.1038\/ncomms13344","article-title":"Macrophage-dependent IL-1\u03b2 production induces cardiac arrhythmias in diabetic mice","volume":"7","author":"Monnerat","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.jacc.2006.01.078","article-title":"Decrease in Circulating Myeloid Dendritic Cell Precursors in Coronary Artery Disease","volume":"48","author":"Yilmaz","year":"2006","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1161\/01.CIR.87.3.909","article-title":"Interstitial dendritic cells of the rat heart. Quantitative and ultrastructural changes in experimental myocardial infarction","volume":"87","author":"Zhang","year":"1993","journal-title":"Circulation"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1234","DOI":"10.1161\/CIRCULATIONAHA.111.052126","article-title":"Regulatory role of dendritic cells in postinfarction healing and left ventricular remodeling","volume":"125","author":"Anzai","year":"2012","journal-title":"Circulation"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5691","DOI":"10.4049\/jimmunol.181.8.5691","article-title":"Differential effects of GM-CSF and G-CSF on infiltration of dendritic cells during early left ventricular remodeling after myocardial infarction","volume":"181","author":"Naito","year":"2008","journal-title":"J. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Gallo, P.M., and Gallucci, S. (2013). The dendritic cell response to classic, emerging, and homeostatic danger signals. Implications for autoimmunity. Front. Immunol., 4.","DOI":"10.3389\/fimmu.2013.00138"},{"key":"ref_25","first-page":"459","article-title":"Human plasmacytoid dendritic cells efficiently cross-present exogenous Ags to CD8+ T cells despite lower Ag uptake than myeloid dendritic cell subsets","volume":"121","author":"Tel","year":"2013","journal-title":"Blood J. Am. Soc. Hematol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4217","DOI":"10.7150\/thno.40663","article-title":"CD8(+) T-cell plasticity regulates vascular regeneration in type-2 diabetes","volume":"10","author":"Liang","year":"2020","journal-title":"Theranostics"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.1038\/s41467-021-21737-9","article-title":"Cytotoxic CD8+ T cells promote granzyme B-dependent adverse post-ischemic cardiac remodeling","volume":"12","author":"Zlatanova","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3365","DOI":"10.4049\/jimmunol.1301522","article-title":"The requirement of CD8+ T cells to initiate and augment acute cardiac inflammatory response to high blood pressure","volume":"192","author":"Ma","year":"2014","journal-title":"J. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.intimp.2016.07.027","article-title":"Depletion of T lymphocytes ameliorates cardiac fibrosis in streptozotocin-induced diabetic cardiomyopathy","volume":"39","author":"Abdullah","year":"2016","journal-title":"Int. Immunopharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1038\/nm.3284","article-title":"B lymphocytes trigger monocyte mobilization and impair heart function after acute myocardial infarction","volume":"19","author":"Zouggari","year":"2013","journal-title":"Nat. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1007\/s00395-021-00886-4","article-title":"Regulatory B cells improve ventricular remodeling after myocardial infarction by modulating monocyte migration","volume":"116","author":"Jiao","year":"2021","journal-title":"Basic Res. Cardiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/s00395-022-00956-1","article-title":"Bone marrow-derived na\u00efve B lymphocytes improve heart function after myocardial infarction: A novel cardioprotective mechanism for empagliflozin","volume":"117","author":"Xu","year":"2022","journal-title":"Basic Res. Cardiol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Salybekov, A.A., Kobayashi, S., and Asahara, T. (2022). Characterization of endothelial progenitor cell: Past, present, and future. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23147697"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1186\/1475-2840-13-101","article-title":"Reduced levels of circulating endothelial progenitor cells in acute myocardial infarction patients with diabetes or pre-diabetes: Accompanying the glycemic continuum","volume":"13","author":"Fernandes","year":"2014","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"665","DOI":"10.6061\/clinics\/2013(05)14","article-title":"Effects of ACE inhibition on endothelial progenitor cell mobilization and prognosis after acute myocardial infarction in type 2 diabetic patients","volume":"68","author":"Sun","year":"2013","journal-title":"Clinics"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Ling, L., Shen, Y., Wang, K., Jiang, C., Fang, C., Ferro, A., Kang, L., and Xu, B. (2012). Worse clinical outcomes in acute myocardial infarction patients with type 2 diabetes mellitus: Relevance to impaired endothelial progenitor cells mobilization. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0050739"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3954","DOI":"10.1016\/j.ijcard.2013.06.053","article-title":"Peri-procedural tight glycemic control during early percutaneous coronary intervention up-regulates endothelial progenitor cell level and differentiation during acute ST-elevation myocardial infarction: Effects on myocardial salvage","volume":"168","author":"Marfella","year":"2013","journal-title":"Int. J. Cardiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1930","DOI":"10.1161\/CIRCRESAHA.116.308366","article-title":"Levels of circulating progenitor cells, cardiovascular outcomes and death: A meta-analysis of prospective observational studies","volume":"118","author":"Rigato","year":"2016","journal-title":"Circ. Res."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Salybekov, A.A., Masuda, H., Miyazaki, K., Sheng, Y., Sato, A., Shizuno, T., Iida, Y., Okada, Y., and Asahara, T. (2019). Dipeptidyl dipeptidase-4 inhibitor recovered ischemia through an increase in vasculogenic endothelial progenitor cells and regeneration-associated cells in diet-induced obese mice. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0205477"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1174","DOI":"10.1111\/aor.13384","article-title":"PEGylated carboxyhemoglobin bovine (SANGUINATE) ameliorates myocardial infarction in a rat model","volume":"42","author":"Kawaguchi","year":"2018","journal-title":"Artif. Organs"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1161\/CIRCRESAHA.115.307778","article-title":"Revisiting cardiac cellular composition","volume":"118","author":"Pinto","year":"2016","journal-title":"Circ. Res."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Salybekov, A.A., Kawaguchi, A.T., Masuda, H., Vorateera, K., Okada, C., and Asahara, T. (2018). Regeneration-associated cells improve recovery from myocardial infarction through enhanced vasculogenesis, anti-inflammation, and cardiomyogenesis. PLoS ONE, 13.","DOI":"10.1101\/396101"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/21\/11833\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:28:12Z","timestamp":1760113692000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/21\/11833"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,4]]},"references-count":42,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2024,11]]}},"alternative-id":["ijms252111833"],"URL":"https:\/\/doi.org\/10.3390\/ijms252111833","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,4]]}}}