Потенциал мононуклеарных клеток периферической крови в лечении пациентов с сахарным диабетом и критической ишемией нижних конечностей с ограниченным эффектом или отсутствием возможности прямой реваскуляризации

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.

1. Jude 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.x

2. Reiber 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.ch28

3. Conte 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.2019.02.016

4. Norgren 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.2006.12.037

5. Uccioli 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/dc09-0831

6. Romiti 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.2008.01.005

7. Meloni 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/jcm10173977

8. Meloni 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.2017.0778

9. Steffel 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.120.046048

10. Giurato 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/10.1177/15347346231191583

11. Armstrong 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/s13047-020-00383-2

12. Вавилов 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/10.24884/1682-6655-2021-20-1-41-49

13. Krasilnikova 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-z

14. Чуган 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/probl13481

15. Torbica 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.2018.12.030

16. Zhao 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/ijms17122085

17. Davis 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-z

18. Rehak 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/jcm11030889

19. Di 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/jamd19.22.4.07

20. Troisi 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/S0392-9590.22.04933-1

21. Simader 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/s41419-019-1974-6

22. Zarubova 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.2022.114233

23. Du 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.12518

24. Salybekov 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-y

25. Copic 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/pharmaceutics14081600

26. Vorstandlechner 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/pharmaceutics15041065

27. Vågesjö 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.120.318380

28. Konieczny 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.abg9302

29. Gurevich 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.201797786

30. Martin 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.2021.06.010

31. Lužnik 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.2000574

32. Kimball 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.118.310703

33. Liang 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.40663

34. Obasanmi 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/cells12030467

35. Liao 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.2024.109003

36. Petroff 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.102645

37. Stachura 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/ijms23158621

38. Theocharidis 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.2023.0126

39. Khanna 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.0009539

40. Wood 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.0091574

41. Wu 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/tkac051

42. Zheng 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.2023.115199

43. Cai 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.2023.04.019

44. Zamboni 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/diagnostics12051137

45. Lehalle 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.2018.09.005

46. Persiani 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.2018.05.036

47. 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.

48. 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.116.309045

49. Zhao 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.2023.1243149

50. Domoto R, Sekiguchi F, Tsubota M, Kawabata A. Macrophage as a Peripheral Pain Regulator. Cells. 2021;10(8):1881. doi: https://doi.org/10.3390/cells10081881

51. van 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.2021.11.020

52. Bonanni 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/biomedicines10051091

53. Ferrari 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.2021.05.013

54. Magenta 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.2021.5006

55. Meechem 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-2023-0282

56. Kočí 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.3056

57. Fromer 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.2017.05.094

58. Cramer 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.2010.0009

59. Navarro 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/scrt438

60. Cai 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.0000000000004028

61. Monami 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/s00592-023-02150-8

62. Dubský 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.2022.888809

63. Leung 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.2018.07.019

64. Jarajapu 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.0093965

65. Rehak 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/jcm13237230

66. De 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.2014.0245

67. Scatena 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/jcm10102213

68. Panunzi 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-y

69. Ragghianti 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/jcm12124148

70. Meloni 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/jcm12196123

71. Meloni 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/s00592-025-02522-2

72. 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.