diaendoСахарный диабетDiabetes mellitus2072-03512072-0378Endocrinology research centre10.14341/DM13466diaendo-13466Research ArticleОБЗОРЫREVIEWSПотенциал мононуклеарных клеток периферической крови в лечении пациентов с сахарным диабетом и критической ишемией нижних конечностей с ограниченным эффектом или отсутствием возможности прямой реваскуляризацииThe potential of peripheral blood mononuclear cells in the treatment of patients with diabetes mellitus and critical lower limb ischemia with limited or no possibility of direct revascularizationhttps://orcid.org/0000-0002-6542-6155БондаренкоО. Н.BondarenkoO. N.

Бондаренко Ольга Николаевна, к.м.н.

Москва

Olga N. Bondarenko, MD, PhD

Moscow

olgafoot@mail.ruhttps://orcid.org/0009-0000-7476-0318ЧуганГ. С.ChuganG. S.

Чуган Глеб Сергеевич 

117292, Москва, улица Дм. Ульянова, д. 11 

Gleb S. Chugan, MD

11 Dm. Ulyanova street, 117292 Moscow

Dkice@mail.ruhttps://orcid.org/0000-0003-3797-9788ЯрославцеваМ. В.YaroslavcevaM. V.

Ярославцева Марианна Викторовна, к.м.н.

Москва

Marianna V. Yaroslavceva, MD, PhD

Moscow

mariannaya79@mail.ruhttps://orcid.org/0000-0002-5031-7183ЕгороваД. Н.EgorovaD. N.

Егорова Дарья Никитична, к.м.н., с.н.с.

Москва

Daria N. Egorova, MD, PhD, senior research associate

Moscow

egoorovadasha@yandex.ruhttps://orcid.org/0000-0001-6581-4521ГалстянГ. Р.GalstyanG. R.

Галстян Гагик Радикович, д.м.н., профессор, член-корреспондент РАН

Scopus Author ID: 6701438348; WoS ResearcherID: B-5925-2017

Москва

Gagik R. Galstyan, MD, PhD, Professor

Scopus Author ID: 6701438348; WoS ResearcherID: B-5925-2017

Moscow

galstyangagik964@gmail.comhttps://orcid.org/0000-0002-0016-6698МасчанА. А.MaschanА. A.

Масчан Алексей Александрович, д.м.н., профессор, член-корреспондент РАН

WoS ResearcherID: A-4792-2019

Москва

Alexey A. Maschan, MD, PhD, Professor

WoS ResearcherID: A-4792-2019

Moscow

amaschan@mail.ruГНЦ РФ ФГБУ «Национальный медицинский исследовательский центр эндокринологии имени академика И.И. Дедова»РоссияEndocrinology Research CentreRussian Federation«Национальный медицинский исследовательский центр детской гематологии, онкологии и иммунологии имени Дмитрия Рогачева»РоссияDmitriy Rogachev National Medical Center of pediatric hematology, oncology and immunologyRussian Federation202601102026294410418Copyright © Бондаренко О.Н., Чуган Г.С., Ярославцева М.В., Егорова Д.Н., Галстян Г.Р., Масчан А.А., 20262026Бондаренко О.Н., Чуган Г.С., Ярославцева М.В., Егорова Д.Н., Галстян Г.Р., Масчан А.А.Bondarenko O.N., Chugan G.S., Yaroslavceva M.V., Egorova D.N., Galstyan G.R., Maschan А.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.dia-endojournals.ru/jour/article/view/13466

Сахарный диабет (СД) является одним из основных факторов риска развития заболеваний артерий нижних конечностей (ЗАНК) с последующим прогрессированием до стадии критической ишемии. Несмотря на достигнутые успехи эндоваскулярных технологий последних лет, риск технической неудачи и осложнений оперативных вмешательств у пациентов с СД и критической ишемией нижних конечностей (КИНК) повышен ввиду наличия осложнений заболевания, а отдаленные результаты восстановления артериальной проходимости существенно хуже, чем в здоровой популяции. При поиске терапевтических альтернатив у таких пациентов все чаще изучается роль иммунных и эндотелиальных клеток, кератиноцитов и фибробластов. В данном обзоре проведен анализ имеющихся на сегодняшний день исследований по использованию аутологичных мононуклеарных клеток периферической крови (МКПК) в лечении пациентов с СД и КИНК. На сегодняшний день убедительно доказана положительная роль МКПК в стимуляции ангиогенеза, поляризации макрофагов от фенотипа M1 к фенотипу M2, а также относительная простота их применения в сравнении с альтернативными методами клеточной терапии. Согласно представленным данным, терапия с применением аутологичных МКПК обоснована и может быть эффективна в реальной клинической практике. Тем не менее необходимы дальнейшие исследования для уточнения методики получения, кратности применения, состава клеточных продуктов на основе МКПК и своевременности их применения.

Diabetes mellitus (DM) is one of the main risk factors for the development of peripheral arterial disease (PAD) with subsequent progression to critical limb ischemia. Despite advances in endovascular technologies in recent years, the risk of technical failure and complications of surgical interventions in patients with DM and critical limb ischemia (CLI) is increased due to the presence of disease complications, and long-term outcomes of arterial patency restoration are significantly worse than those in the healthy population. In the search for therapeutic alternatives in these patients, the role of immune and endothelial cells, keratinocytes, and fibroblasts is increasingly being studied. This review analyzes existing studies on the use of autologous peripheral blood mononuclear cells (PBMNCs) in the treatment of patients with DM and CLI. The positive role of PBMNCs in stimulating angiogenesis and polarizing macrophages from the M1 to M2 phenotype, as well as the relative ease of their use compared to alternative cell therapies, has been convincingly demonstrated. According to the presented data, therapy using autologous PBMNCs is justified and may be effective in real-world clinical practice. However, further research is needed to clarify the production method, frequency of administration, composition of PBMNC-based cell products, and the timing of their use.

синдром диабетической стопызаболевания артерий нижних конечностейангиогенезполяризация макрофаговклеточная терапияdiabetic foot syndromelower extremity arterial diseaseangiogenesismacrophage polarizationcell therapyReferencesJude EB, Eleftheriadou I, Tentolouris N. Peripheral arterial disease in diabetes — a review. Diabet Med. 2010;27(1):4–14. doi: https://doi.org/10.1111/j.1464-5491.2009.02866.xJude EB, Eleftheriadou I, Tentolouris N. Peripheral arterial disease in diabetes — a review. Diabet Med. 2010;27(1):4–14. doi: https://doi.org/10.1111/j.1464-5491.2009.02866.xReiber GE, Ledoux WR. Epidemiology of diabetic foot ulcers and amputations: evidence for prevention. In: Williams R, Herman W, Kinmonth AL, Wareham NJ, eds. The Evidence Base for Diabetes Care. John Wiley & Sons, Ltd.; 2002:641–665. doi: https://doi.org/10.1002/0470846585.ch28Reiber GE, Ledoux WR. Epidemiology of diabetic foot ulcers and amputations: evidence for prevention. In: Williams R, Herman W, Kinmonth AL, Wareham NJ, eds. The Evidence Base for Diabetes Care. John Wiley & Sons, Ltd.; 2002:641–665. doi: https://doi.org/10.1002/0470846585.ch28Conte MS, Bradbury AW, Kolh P, et al. Global vascular guidelines on the management of chronic limb-threatening ischemia. J Vasc Surg. 2019;69(6S):3S–125S.e40. doi: https://doi.org/10.1016/j.jvs.2019.02.016Conte MS, Bradbury AW, Kolh P, et al. Global vascular guidelines on the management of chronic limb-threatening ischemia. J Vasc Surg. 2019;69(6S):3S–125S.e40. doi: https://doi.org/10.1016/j.jvs.2019.02.016Norgren L, Hiatt WR, Dormandy JA, et al. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). J Vasc Surg. 2007;45(suppl S):S5–S67. doi: https://doi.org/10.1016/j.jvs.2006.12.037Norgren L, Hiatt WR, Dormandy JA, et al. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). J Vasc Surg. 2007;45(suppl S):S5–S67. doi: https://doi.org/10.1016/j.jvs.2006.12.037Uccioli L, Gandini R, Giurato L, et al. Long-term outcomes of diabetic patients with critical limb ischemia followed in a tertiary referral diabetic foot clinic. Diabetes Care. 2010;33(5):977–982. doi: https://doi.org/10.2337/dc09-0831Uccioli L, Gandini R, Giurato L, et al. Long-term outcomes of diabetic patients with critical limb ischemia followed in a tertiary referral diabetic foot clinic. Diabetes Care. 2010;33(5):977–982. doi: https://doi.org/10.2337/dc09-0831Romiti M, Albers M, Brochado-Neto FC, Durazzo AES. Meta-analysis of infrapopliteal angioplasty for chronic critical limb ischemia. J Vasc Surg. 2008;47(5):975–981. doi: https://doi.org/10.1016/j.jvs.2008.01.005Romiti M, Albers M, Brochado-Neto FC, Durazzo AES. Meta-analysis of infrapopliteal angioplasty for chronic critical limb ischemia. J Vasc Surg. 2008;47(5):975–981. doi: https://doi.org/10.1016/j.jvs.2008.01.005Meloni M, Morosetti D, Giurato L, et al. Foot Revascularization Avoids Major Amputation in Persons with Diabetes and Ischaemic Foot Ulcers. J Clin Med. 2021;10(17):3977. doi: https://doi.org/10.3390/jcm10173977Meloni M, Morosetti D, Giurato L, et al. Foot Revascularization Avoids Major Amputation in Persons with Diabetes and Ischaemic Foot Ulcers. J Clin Med. 2021;10(17):3977. doi: https://doi.org/10.3390/jcm10173977Meloni M, Izzo V, Giurato L, et al. Recurrence of Critical Limb Ischemia After Endovascular Intervention in Patients with Diabetic Foot Ulcers. Adv Wound Care (New Rochelle). 2018;7(6):171–176. doi: https://doi.org/10.1089/wound.2017.0778Meloni M, Izzo V, Giurato L, et al. Recurrence of Critical Limb Ischemia After Endovascular Intervention in Patients with Diabetic Foot Ulcers. Adv Wound Care (New Rochelle). 2018;7(6):171–176. doi: https://doi.org/10.1089/wound.2017.0778Steffel J, Eikelboom JW, Anand SS, et al. The COMPASS Trial: Net Clinical Benefit of Low-Dose Rivaroxaban Plus Aspirin as Compared With Aspirin in Patients With Chronic Vascular Disease. Circulation. 2020;142(1):40–48. doi: https://doi.org/10.1161/CIRCULATIONAHA.120.046048Steffel J, Eikelboom JW, Anand SS, et al. The COMPASS Trial: Net Clinical Benefit of Low-Dose Rivaroxaban Plus Aspirin as Compared With Aspirin in Patients With Chronic Vascular Disease. Circulation. 2020;142(1):40–48. doi: https://doi.org/10.1161/CIRCULATIONAHA.120.046048Giurato L, Panunzi A, Meloni M, et al. Risk Factors for Ulcer Recurrence in Diabetic Patients Managed by an Integrated Foot Care Protocol. Int J Low Extrem Wounds. 2026;25(1):123–129. doi: https://doi.org/10.1177/15347346231191583Giurato L, Panunzi A, Meloni M, et al. Risk Factors for Ulcer Recurrence in Diabetic Patients Managed by an Integrated Foot Care Protocol. Int J Low Extrem Wounds. 2026;25(1):123–129. doi: https://doi.org/10.1177/15347346231191583Armstrong DG, Swerdlow MA, Armstrong AA, et al. Five year mortality and direct costs of care for people with diabetic foot complications are comparable to cancer. J Foot Ankle Res. 2020;13(1):16. doi: https://doi.org/10.1186/s13047-020-00383-2Armstrong DG, Swerdlow MA, Armstrong AA, et al. Five year mortality and direct costs of care for people with diabetic foot complications are comparable to cancer. J Foot Ankle Res. 2020;13(1):16. doi: https://doi.org/10.1186/s13047-020-00383-2Вавилов В.Н., Зарицкий А.Ю., Полынцев Д.Г., и др. Эффективность мезенхимных стромальных клеток при лечении больных с критической ишемией нижних конечностей // Регионарное кровообращение и микроциркуляция. — 2021. — Т. 20. — № 1. — С. 41–49. doi: https://doi.org/10.24884/1682-6655-2021-20-1-41-49Vavilov VN, Zaritskey AYu, Polyntsev DG, et al. Efficiency of mesenchymal stromal cells (MSCs) in the treatment of patients with critical limb-threatening ischemia. Regional Blood Circulation and Microcirculation. 2021;20(1):41–49. (In Russ.)] doi: https://doi.org/10.24884/1682-6655-2021-20-1-41-49Krasilnikova OA, Baranovskii DS, Lyundup AV, et al. Stem and Somatic Cell Monotherapy for the Treatment of Diabetic Foot Ulcers: Review of Clinical Studies and Mechanisms of Action. Stem Cell Rev Rep. 2022;18(6):1974–1985. doi: https://doi.org/10.1007/s12015-022-10379-zKrasilnikova OA, Baranovskii DS, Lyundup AV, et al. Stem and Somatic Cell Monotherapy for the Treatment of Diabetic Foot Ulcers: Review of Clinical Studies and Mechanisms of Action. Stem Cell Rev Rep. 2022;18(6):1974–1985. doi: https://doi.org/10.1007/s12015-022-10379-zЧуган Г.С., Люндуп А.В., Бондаренко О.Н., Галстян Г.Р. Применение клеточных препаратов для лечения критической ишемии нижних конечностей у пациентов с сахарным диабетом: обзор литературы // Проблемы эндокринологии. — 2024. — Т. 70. — № 4. — С. 4–14. doi: https://doi.org/10.14341/probl13481Chugan GS, Lyundup AV, Bondarenko ON, Galstyan GR. The application of cell products for the treatment of critical limb ischemia in patients with diabetes mellitus: a review of the literature. Problems of Endocrinology. 2024;70(4):4–14. (In Russ.)] doi: https://doi.org/10.14341/probl13481Torbica T, Wicks K, Umehara T, et al. Chronic Inflammation in Response to Injury: Retention of Myeloid Cells in Injured Tissue Is Driven by Myeloid Cell Intrinsic Factors. J Invest Dermatol. 2019;139(7):1583–1592. doi: https://doi.org/10.1016/j.jid.2018.12.030Torbica T, Wicks K, Umehara T, et al. Chronic Inflammation in Response to Injury: Retention of Myeloid Cells in Injured Tissue Is Driven by Myeloid Cell Intrinsic Factors. J Invest Dermatol. 2019;139(7):1583–1592. doi: https://doi.org/10.1016/j.jid.2018.12.030Zhao R, Liang H, Clarke E, et al. Inflammation in Chronic Wounds. Int J Mol Sci. 2016;17(12):2085. doi: https://doi.org/10.3390/ijms17122085Zhao R, Liang H, Clarke E, et al. Inflammation in Chronic Wounds. Int J Mol Sci. 2016;17(12):2085. doi: https://doi.org/10.3390/ijms17122085Davis FM, Kimball A, Boniakowski A, Gallagher K. Dysfunctional Wound Healing in Diabetic Foot Ulcers: New Crossroads. Curr Diab Rep. 2018;18(1):2. doi: https://doi.org/10.1007/s11892-018-0970-zDavis FM, Kimball A, Boniakowski A, Gallagher K. Dysfunctional Wound Healing in Diabetic Foot Ulcers: New Crossroads. Curr Diab Rep. 2018;18(1):2. doi: https://doi.org/10.1007/s11892-018-0970-zRehak L, Giurato L, Meloni M, et al. The Immune-Centric Revolution in the Diabetic Foot: Monocytes and Lymphocytes Role in Wound Healing and Tissue Regeneration-A Narrative Review. J Clin Med. 2022;11(3):889. doi: https://doi.org/10.3390/jcm11030889Rehak L, Giurato L, Meloni M, et al. The Immune-Centric Revolution in the Diabetic Foot: Monocytes and Lymphocytes Role in Wound Healing and Tissue Regeneration-A Narrative Review. J Clin Med. 2022;11(3):889. doi: https://doi.org/10.3390/jcm11030889Di Vieste G, Formenti I, Lodigiani S, et al. Use of autologous peripheral blood mononuclear cells in a case of diabetic foot. The Journal of AMD. 2019;22(4):230–233. doi: https://doi.org/10.36171/jamd19.22.4.07Di Vieste G, Formenti I, Lodigiani S, et al. Use of autologous peripheral blood mononuclear cells in a case of diabetic foot. The Journal of AMD. 2019;22(4):230–233. doi: https://doi.org/10.36171/jamd19.22.4.07Troisi N, D’Oria M, Fernandes E, et al. International Union of Angiology Position Statement on no-option chronic limb threatening ischemia. Int Angiol. 2022;41(5):382–404. doi: https://doi.org/10.23736/S0392-9590.22.04933-1Troisi N, D’Oria M, Fernandes E, et al. International Union of Angiology Position Statement on no-option chronic limb threatening ischemia. Int Angiol. 2022;41(5):382–404. doi: https://doi.org/10.23736/S0392-9590.22.04933-1Simader E, Beer L, Laggner M, et al. Tissue-regenerative potential of the secretome of γ-irradiated peripheral blood mononuclear cells is mediated via TNFRSF1B-induced necroptosis. Cell Death Dis. 2019;10(10):729. doi: https://doi.org/10.1038/s41419-019-1974-6Simader E, Beer L, Laggner M, et al. Tissue-regenerative potential of the secretome of γ-irradiated peripheral blood mononuclear cells is mediated via TNFRSF1B-induced necroptosis. Cell Death Dis. 2019;10(10):729. doi: https://doi.org/10.1038/s41419-019-1974-6Zarubova J, Hasani-Sadrabadi MM, Ardehali R, Li S. Immunoengineering strategies to enhance vascularization and tissue regeneration. Adv Drug Deliv Rev. 2022;184:114233. doi: https://doi.org/10.1016/j.addr.2022.114233Zarubova J, Hasani-Sadrabadi MM, Ardehali R, Li S. Immunoengineering strategies to enhance vascularization and tissue regeneration. Adv Drug Deliv Rev. 2022;184:114233. doi: https://doi.org/10.1016/j.addr.2022.114233Du Cheyne C, Tay H, De Spiegelaere W. The complex TIE between macrophages and angiogenesis. Anat Histol Embryol. 2020;49(5):585–596. doi: https://doi.org/10.1111/ahe.12518Du Cheyne C, Tay H, De Spiegelaere W. The complex TIE between macrophages and angiogenesis. Anat Histol Embryol. 2020;49(5):585–596. doi: https://doi.org/10.1111/ahe.12518Salybekov AA, Hassanpour M, Kobayashi S, Asahara T. Therapeutic application of regeneration-associated cells: a novel source of regenerative medicine. Stem Cell Res Ther. 2023;14(1):191. doi: https://doi.org/10.1186/s13287-023-03428-ySalybekov AA, Hassanpour M, Kobayashi S, Asahara T. Therapeutic application of regeneration-associated cells: a novel source of regenerative medicine. Stem Cell Res Ther. 2023;14(1):191. doi: https://doi.org/10.1186/s13287-023-03428-yCopic D, Direder M, Schossleitner K, et al. Paracrine Factors of Stressed Peripheral Blood Mononuclear Cells Activate Proangiogenic and Anti-Proteolytic Processes in Whole Blood Cells and Protect the Endothelial Barrier. Pharmaceutics. 2022;14(8):1600. doi: https://doi.org/10.3390/pharmaceutics14081600Copic D, Direder M, Schossleitner K, et al. Paracrine Factors of Stressed Peripheral Blood Mononuclear Cells Activate Proangiogenic and Anti-Proteolytic Processes in Whole Blood Cells and Protect the Endothelial Barrier. Pharmaceutics. 2022;14(8):1600. doi: https://doi.org/10.3390/pharmaceutics14081600Vorstandlechner V, Copic D, Klas K, et al. The Secretome of Irradiated Peripheral Mononuclear Cells Attenuates Hypertrophic Skin Scarring. Pharmaceutics. 2023;15(4):1065. doi: https://doi.org/10.3390/pharmaceutics15041065Vorstandlechner V, Copic D, Klas K, et al. The Secretome of Irradiated Peripheral Mononuclear Cells Attenuates Hypertrophic Skin Scarring. Pharmaceutics. 2023;15(4):1065. doi: https://doi.org/10.3390/pharmaceutics15041065Vågesjö E, Parv K, Ahl D, et al. Perivascular Macrophages Regulate Blood Flow Following Tissue Damage. Circ Res. 2021;128(11):1694–1707. doi: https://doi.org/10.1161/CIRCRESAHA.120.318380Vågesjö E, Parv K, Ahl D, et al. Perivascular Macrophages Regulate Blood Flow Following Tissue Damage. Circ Res. 2021;128(11):1694–1707. doi: https://doi.org/10.1161/CIRCRESAHA.120.318380Konieczny P, Xing Y, Sidhu I, et al. Interleukin-17 governs hypoxic adaptation of injured epithelium. Science. 2022;377(6602):eabg9302. doi: https://doi.org/10.1126/science.abg9302Konieczny P, Xing Y, Sidhu I, et al. Interleukin-17 governs hypoxic adaptation of injured epithelium. Science. 2022;377(6602):eabg9302. doi: https://doi.org/10.1126/science.abg9302Gurevich DB, Severn CE, Twomey C, et al. Live imaging of wound angiogenesis reveals macrophage orchestrated vessel sprouting and regression. EMBO J. 2018;37(13):e97786. doi: https://doi.org/10.15252/embj.201797786Gurevich DB, Severn CE, Twomey C, et al. Live imaging of wound angiogenesis reveals macrophage orchestrated vessel sprouting and regression. EMBO J. 2018;37(13):e97786. doi: https://doi.org/10.15252/embj.201797786Martin P, Gurevich DB. Macrophage regulation of angiogenesis in health and disease. Semin Cell Dev Biol. 2021;119:101–110. doi: https://doi.org/10.1016/j.semcdb.2021.06.010Martin P, Gurevich DB. Macrophage regulation of angiogenesis in health and disease. Semin Cell Dev Biol. 2021;119:101–110. doi: https://doi.org/10.1016/j.semcdb.2021.06.010Lužnik Z, Anchouche S, Dana R, Yin J. Regulatory T Cells in Angiogenesis. J Immunol. 2020;205(10):2557–2565. doi: https://doi.org/10.4049/jimmunol.2000574Lužnik Z, Anchouche S, Dana R, Yin J. Regulatory T Cells in Angiogenesis. J Immunol. 2020;205(10):2557–2565. doi: https://doi.org/10.4049/jimmunol.2000574Kimball A, Schaller M, Joshi A, et al. Ly6CHi Blood Monocyte/ Macrophage Drive Chronic Inflammation and Impair Wound Healing in Diabetes Mellitus. Arterioscler Thromb Vasc Biol. 2018;38(5):1102–1114. doi: https://doi.org/10.1161/ATVBAHA.118.310703Kimball A, Schaller M, Joshi A, et al. Ly6CHi Blood Monocyte/ Macrophage Drive Chronic Inflammation and Impair Wound Healing in Diabetes Mellitus. Arterioscler Thromb Vasc Biol. 2018;38(5):1102–1114. doi: https://doi.org/10.1161/ATVBAHA.118.310703Liang C, Yang KY, Chan VW, et al. CD8+ T-cell plasticity regulates vascular regeneration in type-2 diabetes. Theranostics. 2020;10(9):4217–4232. doi: https://doi.org/10.7150/thno.40663Liang C, Yang KY, Chan VW, et al. CD8+ T-cell plasticity regulates vascular regeneration in type-2 diabetes. Theranostics. 2020;10(9):4217–4232. doi: https://doi.org/10.7150/thno.40663Obasanmi G, Lois N, Armstrong D, et al. Peripheral Blood Mononuclear Cells from Patients with Type 1 Diabetes and Diabetic Retinopathy Produce Higher Levels of IL-17A, IL-10 and IL-6 and Lower Levels of IFN-γ—A Pilot Study. Cells. 2023;12(3):467. doi: https://doi.org/10.3390/cells12030467Obasanmi G, Lois N, Armstrong D, et al. Peripheral Blood Mononuclear Cells from Patients with Type 1 Diabetes and Diabetic Retinopathy Produce Higher Levels of IL-17A, IL-10 and IL-6 and Lower Levels of IFN-γ—A Pilot Study. Cells. 2023;12(3):467. doi: https://doi.org/10.3390/cells12030467Liao D, Fan W, Li N, et al. A single cell atlas of circulating immune cells involved in diabetic retinopathy. iScience. 2024;27(2):109003. doi: https://doi.org/10.1016/j.isci.2024.109003Liao D, Fan W, Li N, et al. A single cell atlas of circulating immune cells involved in diabetic retinopathy. iScience. 2024;27(2):109003. doi: https://doi.org/10.1016/j.isci.2024.109003Petroff A. Inflammation-Associated Wound Healing through a Monocytic Lens. In: Kumar V, ed. Macrophages - Celebrating 140 Years of Discovery. IntechOpen; 2022. doi: https://doi.org/10.5772/intechopen.102645Petroff A. Inflammation-Associated Wound Healing through a Monocytic Lens. In: Kumar V, ed. Macrophages - Celebrating 140 Years of Discovery. IntechOpen; 2022. doi: https://doi.org/10.5772/intechopen.102645Stachura A, Khanna I, Krysiak P, et al. Wound Healing Impairment in Type 2 Diabetes Model of Leptin-Deficient Mice-A Mechanistic Systematic Review. Int J Mol Sci. 2022;23(15):8621. doi: https://doi.org/10.3390/ijms23158621Stachura A, Khanna I, Krysiak P, et al. Wound Healing Impairment in Type 2 Diabetes Model of Leptin-Deficient Mice-A Mechanistic Systematic Review. Int J Mol Sci. 2022;23(15):8621. doi: https://doi.org/10.3390/ijms23158621Theocharidis G, Sumpio B, Wang E, et al. Use of Serum Protein Measurements as Biomarkers that Can Predict the Outcome of Diabetic Foot Ulceration. Adv Wound Care (New Rochelle). 2024;13(9):426–434. doi: https://doi.org/10.1089/wound.2023.0126Theocharidis G, Sumpio B, Wang E, et al. Use of Serum Protein Measurements as Biomarkers that Can Predict the Outcome of Diabetic Foot Ulceration. Adv Wound Care (New Rochelle). 2024;13(9):426–434. doi: https://doi.org/10.1089/wound.2023.0126Khanna S, Biswas S, Shang Y, et al. Macrophage dysfunction impairs resolution of inflammation in the wounds of diabetic mice. PLoS One. 2010;5(3):e9539. doi: https://doi.org/10.1371/journal.pone.0009539Khanna S, Biswas S, Shang Y, et al. Macrophage dysfunction impairs resolution of inflammation in the wounds of diabetic mice. PLoS One. 2010;5(3):e9539. doi: https://doi.org/10.1371/journal.pone.0009539Wood S, Jayaraman V, Huelsmann EJ, et al. Pro-inflammatory chemokine CCL2 (MCP–1) promotes healing in diabetic wounds by restoring the macrophage response. PLoS One. 2014;9(3):e91574. doi: https://doi.org/10.1371/journal.pone.0091574Wood S, Jayaraman V, Huelsmann EJ, et al. Pro-inflammatory chemokine CCL2 (MCP–1) promotes healing in diabetic wounds by restoring the macrophage response. PLoS One. 2014;9(3):e91574. doi: https://doi.org/10.1371/journal.pone.0091574Wu X, He W, Mu X, et al. Macrophage polarization in diabetic wound healing. Burns Trauma. 2022;10:tkac051. doi: https://doi.org/10.1093/burnst/tkac051Wu X, He W, Mu X, et al. Macrophage polarization in diabetic wound healing. Burns Trauma. 2022;10:tkac051. doi: https://doi.org/10.1093/burnst/tkac051Zheng H, Cheng X, Jin L, et al. Recent advances in strategies to target the behavior of macrophages in wound healing. Biomed Pharmacother. 2023;165:115199. doi: https://doi.org/10.1016/j.biopha.2023.115199Zheng H, Cheng X, Jin L, et al. Recent advances in strategies to target the behavior of macrophages in wound healing. Biomed Pharmacother. 2023;165:115199. doi: https://doi.org/10.1016/j.biopha.2023.115199Cai Y, Chen K, Liu C, Qu X. Harnessing strategies for enhancing diabetic wound healing from the perspective of spatial inflammation patterns. Bioact Mater. 2023;28:243–254. doi: https://doi.org/10.1016/j.bioactmat.2023.04.019Cai Y, Chen K, Liu C, Qu X. Harnessing strategies for enhancing diabetic wound healing from the perspective of spatial inflammation patterns. Bioact Mater. 2023;28:243–254. doi: https://doi.org/10.1016/j.bioactmat.2023.04.019Zamboni M, Pedriali M, Ferretto L, et al. PBMNCs Treatment in Critical Limb Ischemia and Candidate Biomarkers of Efficacy. Diagnostics (Basel). 2022;12(5):1137. doi: https://doi.org/10.3390/diagnostics12051137Zamboni M, Pedriali M, Ferretto L, et al. PBMNCs Treatment in Critical Limb Ischemia and Candidate Biomarkers of Efficacy. Diagnostics (Basel). 2022;12(5):1137. doi: https://doi.org/10.3390/diagnostics12051137Lehalle B, Jan P, Stoltz JF. Diabetic patients on Rutherford’s stage 5 is the best indication of stem cell therapy in peripheral artery disease: a retrospective study on 367 patients. Journal of Cellular Immunotherapy. 2018;4(1):18–21. doi: https://doi.org/10.1016/j.jocit.2018.09.005Lehalle B, Jan P, Stoltz JF. Diabetic patients on Rutherford’s stage 5 is the best indication of stem cell therapy in peripheral artery disease: a retrospective study on 367 patients. Journal of Cellular Immunotherapy. 2018;4(1):18–21. doi: https://doi.org/10.1016/j.jocit.2018.09.005Persiani F, Paolini A, Camilli D, et al. Peripheral Blood Mononuclear Cells Therapy for Treatment of Lower Limb Ischemia in Diabetic Patients: A Single-Center Experience. Ann Vasc Surg. 2018;53:190–196. doi: https://doi.org/10.1016/j.avsg.2018.05.036Persiani F, Paolini A, Camilli D, et al. Peripheral Blood Mononuclear Cells Therapy for Treatment of Lower Limb Ischemia in Diabetic Patients: A Single-Center Experience. Ann Vasc Surg. 2018;53:190–196. doi: https://doi.org/10.1016/j.avsg.2018.05.036Di Pardo A, Cappello E, Pepe G, et al. Infusion of autologousperipheral blood mononuclear cells: a new approach for limb salvage in patients with diabetes. In: Proceedings of the 7th International Diabetic Foot Congress Abu Dhabi; December 4–8, 2017; Abu Dhabi, United Arab Emirates. IFD Congress; 2017.Di Pardo A, Cappello E, Pepe G, et al. Infusion of autologousperipheral blood mononuclear cells: a new approach for limb salvage in patients with diabetes. In: Proceedings of the 7th International Diabetic Foot Congress Abu Dhabi; December 4–8, 2017; Abu Dhabi, United Arab Emirates. IFD Congress; 2017.Rigato M, Monami M, Fadini GP. Autologous Cell Therapy for Peripheral Arterial Disease: Systematic Review and Meta-Analysis of Randomized, Nonrandomized, and Noncontrolled Studies. Circ Res. 2017;120(8):1326–1340. doi: https://doi.org/10.1161/CIRCRESAHA.116.309045Rigato M, Monami M, Fadini GP. Autologous Cell Therapy for Peripheral Arterial Disease: Systematic Review and Meta-Analysis of Randomized, Nonrandomized, and Noncontrolled Studies. Circ Res. 2017;120(8):1326–1340. doi: https://doi.org/10.1161/CIRCRESAHA.116.309045Zhao W, Ma L, Deng D, et al. M2 macrophage polarization: a potential target in pain relief. Front Immunol. 2023;14:1243149. doi: https://doi.org/10.3389/fimmu.2023.1243149Zhao W, Ma L, Deng D, et al. M2 macrophage polarization: a potential target in pain relief. Front Immunol. 2023;14:1243149. doi: https://doi.org/10.3389/fimmu.2023.1243149Domoto R, Sekiguchi F, Tsubota M, Kawabata A. Macrophage as a Peripheral Pain Regulator. Cells. 2021;10(8):1881. doi: https://doi.org/10.3390/cells10081881Domoto R, Sekiguchi F, Tsubota M, Kawabata A. Macrophage as a Peripheral Pain Regulator. Cells. 2021;10(8):1881. doi: https://doi.org/10.3390/cells10081881van der Vlist M, Raoof R, Willemen HLDM, et al. Macrophages transfer mitochondria to sensory neurons to resolve inflammatory pain. Neuron. 2022;110(4):613–626.e9. doi: https://doi.org/10.1016/j.neuron.2021.11.020van der Vlist M, Raoof R, Willemen HLDM, et al. Macrophages transfer mitochondria to sensory neurons to resolve inflammatory pain. Neuron. 2022;110(4):613–626.e9. doi: https://doi.org/10.1016/j.neuron.2021.11.020Bonanni M, Rehak L, Massaro G, et al. Autologous Immune Cell-Based Regenerative Therapies to Treat Vasculogenic Erectile Dysfunction: Is the Immuno-Centric Revolution Ready for the Prime Time? Biomedicines. 2022;10(5):1091. doi: https://doi.org/10.3390/biomedicines10051091Bonanni M, Rehak L, Massaro G, et al. Autologous Immune Cell-Based Regenerative Therapies to Treat Vasculogenic Erectile Dysfunction: Is the Immuno-Centric Revolution Ready for the Prime Time? Biomedicines. 2022;10(5):1091. doi: https://doi.org/10.3390/biomedicines10051091Ferrari I, Vagnozzi RJ. Mechanisms and strategies for a therapeutic cardiac immune response. J Mol Cell Cardiol. 2021;158:82–88. doi: https://doi.org/10.1016/j.yjmcc.2021.05.013Ferrari I, Vagnozzi RJ. Mechanisms and strategies for a therapeutic cardiac immune response. J Mol Cell Cardiol. 2021;158:82–88. doi: https://doi.org/10.1016/j.yjmcc.2021.05.013Magenta A, Florio MC, Ruggeri M, Furgiuele S. Autologous cell therapy in diabetes-associated critical limb ischemia: From basic studies to clinical outcomes (Review). Int J Mol Med. 2021;48(3):173. doi: https://doi.org/10.3892/ijmm.2021.5006Magenta A, Florio MC, Ruggeri M, Furgiuele S. Autologous cell therapy in diabetes-associated critical limb ischemia: From basic studies to clinical outcomes (Review). Int J Mol Med. 2021;48(3):173. doi: https://doi.org/10.3892/ijmm.2021.5006Meechem MB, Jadli AS, Patel VB. Uncovering the link between diabetes and cardiovascular diseases: insights from adiposederived stem cells. Can J Physiol Pharmacol. 2024;102(4):229–241. doi: https://doi.org/10.1139/cjpp-2023-0282Meechem MB, Jadli AS, Patel VB. Uncovering the link between diabetes and cardiovascular diseases: insights from adiposederived stem cells. Can J Physiol Pharmacol. 2024;102(4):229–241. doi: https://doi.org/10.1139/cjpp-2023-0282Kočí Z, Turnovcová K, Dubský M, et al. Characterization of human adipose tissue-derived stromal cells isolated from diabetic patient’s distal limbs with critical ischemia. Cell Biochem Funct. 2014;32(7):597–604. doi: https://doi.org/10.1002/cbf.3056Kočí Z, Turnovcová K, Dubský M, et al. Characterization of human adipose tissue-derived stromal cells isolated from diabetic patient’s distal limbs with critical ischemia. Cell Biochem Funct. 2014;32(7):597–604. doi: https://doi.org/10.1002/cbf.3056Fromer MW, Chang S, Hagaman ALR, et al. The endothelial cell secretome as a novel treatment to prime adipose-derived stem cells for improved wound healing in diabetes. J Vasc Surg. 2018;68(1):234–244. doi: https://doi.org/10.1016/j.jvs.2017.05.094Fromer MW, Chang S, Hagaman ALR, et al. The endothelial cell secretome as a novel treatment to prime adipose-derived stem cells for improved wound healing in diabetes. J Vasc Surg. 2018;68(1):234–244. doi: https://doi.org/10.1016/j.jvs.2017.05.094Cramer C, Freisinger E, Jones RK, et al. Persistent high glucose concentrations alter the regenerative potential of mesenchymal stem cells. Stem Cells Dev. 2010;19(12):1875–1884. doi: https://doi.org/10.1089/scd.2010.0009Cramer C, Freisinger E, Jones RK, et al. Persistent high glucose concentrations alter the regenerative potential of mesenchymal stem cells. Stem Cells Dev. 2010;19(12):1875–1884. doi: https://doi.org/10.1089/scd.2010.0009Navarro A, Marín S, Riol N, et al. Human adipose tissue-resident monocytes exhibit an endothelial-like phenotype and display angiogenic properties. Stem Cell Res Ther. 2014;5(2):50. doi: https://doi.org/10.1186/scrt438Navarro A, Marín S, Riol N, et al. Human adipose tissue-resident monocytes exhibit an endothelial-like phenotype and display angiogenic properties. Stem Cell Res Ther. 2014;5(2):50. doi: https://doi.org/10.1186/scrt438Cai J, Feng J, Liu K, et al. Early Macrophage Infiltration Improves Fat Graft Survival by Inducing Angiogenesis and Hematopoietic Stem Cell Recruitment. Plast Reconstr Surg. 2018;141(2):376–386. doi: https://doi.org/10.1097/PRS.0000000000004028Cai J, Feng J, Liu K, et al. Early Macrophage Infiltration Improves Fat Graft Survival by Inducing Angiogenesis and Hematopoietic Stem Cell Recruitment. Plast Reconstr Surg. 2018;141(2):376–386. doi: https://doi.org/10.1097/PRS.0000000000004028Monami M, Scatena A, Miranda C, et al. Development of the Italian clinical practice guidelines for the treatment of diabetic foot syndrome: design and methodological aspects. Acta Diabetol. 2023;60(11):1449–1469. doi: https://doi.org/10.1007/s00592-023-02150-8Monami M, Scatena A, Miranda C, et al. Development of the Italian clinical practice guidelines for the treatment of diabetic foot syndrome: design and methodological aspects. Acta Diabetol. 2023;60(11):1449–1469. doi: https://doi.org/10.1007/s00592-023-02150-8Dubský M, Husáková J, Bem R, et al. Comparison of the impact of autologous cell therapy and conservative standard treatment on tissue oxygen supply and course of the diabetic foot in patients with chronic limb-threatening ischemia: A randomized controlled trial. Front Endocrinol (Lausanne). 2022;13:888809. doi: https://doi.org/10.3389/fendo.2022.888809Dubský M, Husáková J, Bem R, et al. Comparison of the impact of autologous cell therapy and conservative standard treatment on tissue oxygen supply and course of the diabetic foot in patients with chronic limb-threatening ischemia: A randomized controlled trial. Front Endocrinol (Lausanne). 2022;13:888809. doi: https://doi.org/10.3389/fendo.2022.888809Leung OM, Li J, Li X, et al. Regulatory T Cells Promote Apelin-Mediated Sprouting Angiogenesis in Type 2 Diabetes. Cell Rep. 2018;24(6):1610–1626. doi: https://doi.org/10.1016/j.celrep.2018.07.019Leung OM, Li J, Li X, et al. Regulatory T Cells Promote ApelinMediated Sprouting Angiogenesis in Type 2 Diabetes. Cell Rep. 2018;24(6):1610–1626. doi: https://doi.org/10.1016/j.celrep.2018.07.019Jarajapu YP, Hazra S, Segal M, et al. Vasoreparative dysfunction of CD34+ cells in diabetic individuals involves hypoxic desensitization and impaired autocrine/paracrine mechanisms. PLoS One. 2014;9(4):e93965. doi: https://doi.org/10.1371/journal.pone.0093965Jarajapu YP, Hazra S, Segal M, et al. Vasoreparative dysfunction of CD34+ cells in diabetic individuals involves hypoxic desensitization and impaired autocrine/paracrine mechanisms. PLoS One. 2014;9(4):e93965. doi: https://doi.org/10.1371/journal.pone.0093965Rehak L, Giurato L, Monami M, et al. The Immune-Centric Revolution Translated into Clinical Application: Peripheral Blood Mononuclear Cell (PBMNC) Therapy in Diabetic Patients with No-Option Critical Limb-Threatening Ischemia (NO-CLTI)-Rationale and Meta-Analysis of Observational Studies. J Clin Med. 2024;13(23):7230. doi: https://doi.org/10.3390/jcm13237230Rehak L, Giurato L, Monami M, et al. The Immune-Centric Revolution Translated into Clinical Application: Peripheral Blood Mononuclear Cell (PBMNC) Therapy in Diabetic Patients with No-Option Critical Limb-Threatening Ischemia (NO-CLTI)-Rationale and MetaAnalysis of Observational Studies. J Clin Med. 2024;13(23):7230. doi: https://doi.org/10.3390/jcm13237230De Angelis B, Gentile P, Orlandi F, et al. Limb rescue: a new autologous-peripheral blood mononuclear cells technology in critical limb ischemia and chronic ulcers. Tissue Eng Part C Methods. 2015;21(5):423–435. doi: https://doi.org/10.1089/ten.TEC.2014.0245De Angelis B, Gentile P, Orlandi F, et al. Limb rescue: a new autologous-peripheral blood mononuclear cells technology in critical limb ischemia and chronic ulcers. Tissue Eng Part C Methods. 2015;21(5):423–435. doi: https://doi.org/10.1089/ten.TEC.2014.0245Scatena A, Petruzzi P, Maioli F, et al. Autologous Peripheral Blood Mononuclear Cells for Limb Salvage in Diabetic Foot Patients with No-Option Critical Limb Ischemia. J Clin Med. 2021;10(10):2213. doi: https://doi.org/10.3390/jcm10102213Scatena A, Petruzzi P, Maioli F, et al. Autologous Peripheral Blood Mononuclear Cells for Limb Salvage in Diabetic Foot Patients with No-Option Critical Limb Ischemia. J Clin Med. 2021;10(10):2213. doi: https://doi.org/10.3390/jcm10102213Panunzi A, Madotto F, Sangalli E, et al. Results of a prospective observational study of autologous peripheral blood mononuclear cell therapy for no-option critical limb-threatening ischemia and severe diabetic foot ulcers. Cardiovasc Diabetol. 2022;21(1):196. doi: https://doi.org/10.1186/s12933-022-01629-yPanunzi A, Madotto F, Sangalli E, et al. Results of a prospective observational study of autologous peripheral blood mononuclear cell therapy for no-option critical limb-threatening ischemia and severe diabetic foot ulcers. Cardiovasc Diabetol. 2022;21(1):196. doi: https://doi.org/10.1186/s12933-022-01629-yRagghianti B, Berardi BM, Mannucci E, Monami M. Autologous Peripheral Blood Mononuclear Cells in Patients with Small Artery Disease and Diabetic Foot Ulcers: Efficacy, Safety, and Economic Evaluation. J Clin Med. 2023;12(12):4148. doi: https://doi.org/10.3390/jcm12124148Ragghianti B, Berardi BM, Mannucci E, Monami M. Autologous Peripheral Blood Mononuclear Cells in Patients with Small Artery Disease and Diabetic Foot Ulcers: Efficacy, Safety, and Economic Evaluation. J Clin Med. 2023;12(12):4148. doi: https://doi.org/10.3390/jcm12124148Meloni M, Giurato L, Andreadi A, et al. Peripheral Blood Mononuclear Cells: A New Frontier in the Management of Patients with Diabetes and No-Option Critical Limb Ischaemia. J Clin Med. 2023;12(19):6123. doi: https://doi.org/10.3390/jcm12196123Meloni M, Giurato L, Andreadi A, et al. Peripheral Blood Mononuclear Cells: A New Frontier in the Management of Patients with Diabetes and No-Option Critical Limb Ischaemia. J Clin Med. 2023;12(19):6123. doi: https://doi.org/10.3390/jcm12196123Meloni M, Bellizzi E, Uccioli L, et al. Predictive factors of major amputation in patients with diabetic foot ulcers treated by peripheral blood mononuclear cells. Acta Diabetol. 2025;62(11):1907–1913. doi: https://doi.org/10.1007/s00592-025-02522-2Meloni M, Bellizzi E, Uccioli L, et al. Predictive factors of major amputation in patients with diabetic foot ulcers treated by peripheral blood mononuclear cells. Acta Diabetol. 2025;62(11):1907–1913. doi: https://doi.org/10.1007/s00592-025-02522-2Hendri, Suhartono R, Kekalih A, et al. Healing rate comparison of revascularized and non-revascularized diabetic foot ulcers with peripheral arterial disease. Surg Open Sci. 2023;16:235–241. doi: https://doi.org/10.1016/j.sopen.2023.11.008.Hendri, Suhartono R, Kekalih A, et al. Healing rate comparison of revascularized and non-revascularized diabetic foot ulcers with peripheral arterial disease. Surg Open Sci. 2023;16:235–241. doi: https://doi.org/10.1016/j.sopen.2023.11.008

The authors declare that there are no conflicts of interest present.