This current opinion article critically evaluates the efficacy of autologous cell therapy (ACT) for chronic limb-threatening ischemia (CLTI), especially in people with diabetes who are not candidates for standard revascularization. This treatment approach has been used in 'no-option' CLTI in the last two decades and more than 1700 patients have received ACT worldwide. Here we analyze the level of published evidence of ACT as well as our experience with this treatment method. Many studies have shown that ACT is safe and an effective method for patients with the most severe lower limb ischemia. However, some trials did not show any benefit of ACT, and there is some heterogeneity in the types of injected cells, route of administration and assessed endpoints. Nevertheless, we believe that ACT plays an important role in a comprehensive treatment of patients with diabetic foot and severe ischemia.

• MeSH
• Amputation, Surgical MeSH
• Cell- and Tissue-Based Therapy MeSH
• Diabetes Mellitus * MeSH
• Diabetic Foot * therapy   MeSH
• Ischemia etiology   therapy   MeSH
• Humans MeSH
• Retrospective Studies MeSH
• Risk Factors MeSH
• Treatment Outcome MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

BACKGROUND: Diabetic patients (DPs) with foot ulcers can receive autologous cell therapy (ACT) as a last therapeutic option. Even DPs who have undergone organ transplantation and are using immunosuppressive (IS) drugs can be treated by ACT. The aim of our study was to analyze the effects of IS drugs on the characteristics of bone marrow-derived stem cells (BM-MSCs). METHODS: The cells were isolated from the bone marrow of DPs, cultivated for 14-18 days, and phenotypically characterized using flow cytometry. These precursor cells were cultured in the presence of various IS drugs. The impact of IS drugs on metabolic activity was measured using a WST-1 assay, and the expression of genes for immunoregulatory molecules was detected through RT-PCR. Cell death was analyzed through the use of flow cytometry, and the production of cytokines was determined by ELISA. RESULTS: The mononuclear fraction of cultured cells contained mesenchymal stem cells (CD45-CD73+CD90+CD105+), myeloid angiogenic cells (CD45+CD146-), and endothelial colony-forming cells (CD45-CD146+). IS drugs inhibited metabolic activity, the expression of genes for immunoregulatory molecules, the production of cytokines, and the viability of the cells. CONCLUSIONS: The results indicate that IS drugs in a dose-dependent manner had a negative impact on the properties of BM-MSCs used to treat ischemic diabetic foot ulcers, and that these drugs could affect the therapeutic potential of BM-MSCs.

• Keywords
• cell-based therapies, diabetes, diabetic foot ulcers, immunosuppressive drugs,
• Publication type
• Journal Article MeSH

BACKGROUND: Autologous cell therapy (ACT) is a new treatment method for patients with diabetes and no-option chronic limb-threatening ischemia (NO-CLTI). We aimed to assess the impact of ACT on NO-CLTI in comparison with standard treatment (ST) in a randomized controlled trial. METHODS: Diabetic patients with NO-CLTI were randomized to receive either ACT (n=21) or ST (n=19). After 12 weeks, those in the ST group, who did not improve were treated with ACT. The effect of ACT on ischemia and wound healing was assessed by changes in transcutaneous oxygen pressure (TcPO2) and the number of healed patients at 12 weeks. Pain was evaluated by Visual Analogue Scale (VAS). Amputation rates and amputation-free survival (AFS) were assessed in both groups. RESULTS: During the first 12 weeks, TcPO2 increased in the ACT group from 20.8 ± 9.6 to 41.9 ± 18.3 mm Hg (p=0.005) whereas there was no change in the ST group (from 21.2 ± 11.4 to 23.9 ± 13.5 mm Hg). Difference in TcPO2 in the ACT group compared to ST group was 21.1 mm Hg (p=0.034) after 12 weeks. In the period from week 12 to week 24, when ST group received ACT, the TcPO2 in this group increased from 20.1 ± 13.9 to 41.9 ± 14.8 (p=0.005) while it did not change significantly in the ACT in this period. At 24 weeks, there was no significant difference in mean TcPO2 between the two groups. Wound healing was greater at 12 weeks in the ACT group compared to the ST group (5/16 vs. 0/13, p=0.048). Pain measured using VAS was reduced in the ACT group after 12 weeks compared to the baseline, and the difference in scores was again significant (p<0.001), but not in the ST group. There was no difference in rates of major amputation and AFS between ACT and ST groups at 12 weeks. CONCLUSIONS: This study has showed that ACT treatment in patients with no-option CLTI and diabetic foot significantly improved limb ischemia and wound healing after 12 weeks compared to conservative standard therapy. Larger randomized controlled trials are needed to study the benefits of ACT in patients with NO-CLTI and diabetic foot disease. TRIAL REGISTRATION: The trial was registered in the National Board of Health (EudraCT 2016-001397-15).

• Keywords
• autologous cell therapy, chronic limb-threatening ischemia, diabetic foot, major amputation of lower extremity, revascularization,
• MeSH
• Pain MeSH
• Cell- and Tissue-Based Therapy MeSH
• Chronic Limb-Threatening Ischemia MeSH
• Diabetes Mellitus * MeSH
• Diabetic Foot * therapy   MeSH
• Ischemia therapy   MeSH
• Oxygen MeSH
• Humans MeSH
• Randomized Controlled Trials as Topic MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Oxygen MeSH

INTRODUCTION: Autologous cell therapy (ACT) is one of the last options for limb salvage in patients with chronic limb-threatening ischemia (CLTI) and diabetic foot ulcers (DFU). However, some patients may still undergo a major amputation even after ACT, but the risk factors for this are not known. Therefore, the aim of our study was to assess the risk factors for major amputation in patients with CLTI and DFU during a 2-year follow-up after ACT. METHODS: One hundred and thirteen patients after ACT were included in our study and divided into two groups: Group 1 with major amputation (AMP; n = 37) and Group 2 without amputation (nAMP, n = 76). The risk factors for major amputation were evaluated before ACT and included factors relating to the patient, the DFU, and the cell product. RESULTS: The AMP group had significantly higher C-reactive protein (CRP) levels compared to the nAMP group (22.7 vs. 10.7 mg/L, p = 0.024). In stepwise logistic regression, independent predictors for major amputation were mutation of the gene for methylenetetrahydrofolate reductase (MTHFR) with heterozygote and homozygote polymorphism 1298 (OR 4.33 [95% CI 1.05-17.6]), smoking (OR 3.83 [95% CI 1.18-12.5]), and CRP > 10 mg/L (OR 2.76 [95% CI 0.93-8.21]). Lower transcutaneous oxygen pressure (TcPO2) values were observed in AMP patients compared to the nAMP group at one month (24.5 vs. 33.2, p = 0.012) and at 3 months (31.1 vs. 40.9, p = 0.009) after ACT. CONCLUSION: Our study showed that the risk for major amputation after ACT in patients with CLTI and DFU is increased by the presence of MTHFR heterozygote and homozygote gene mutations, smoking, and higher CRP at baseline. Lower TcPO2 at one and 3 months after ACT may also have a predictive value. Therefore, it is necessary to stop smoking before ACT, treat any infection, and, above all, consider antiaggregation or anticoagulant treatment after the procedure.

• MeSH
• Adenosine Monophosphate MeSH
• Amputation, Surgical MeSH
• Cell- and Tissue-Based Therapy MeSH
• Chronic Limb-Threatening Ischemia MeSH
• Diabetes Mellitus * MeSH
• Diabetic Foot * surgery   MeSH
• Wound Healing MeSH
• Ischemia surgery   MeSH
• Humans MeSH
• Retrospective Studies MeSH
• Risk Factors MeSH
• Treatment Outcome MeSH
• Limb Salvage MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Adenosine Monophosphate MeSH

Endothelial progenitors are a population of cells with the inherent capacity to differentiate into mature endothelial cells and proangiogenic paracrine action. These characteristics have led to extensive studies being performed and tested in the treatment of tissue ischemia. The natural course of diabetes mellitus (DM) results in multiple areas of vascular damage. Thus endothelial progenitor cells'(EPCs) beneficial potential is particularly desirable in diabetic patients. In this review, we summarize contemporary knowledge of EPC biology in DM. It has been shown that EPC functions are considerably impaired by DM. The presence of peripheral arterial disease (PAD) seems to further exacerbate the deficiencies of EPCs. However, studies examining EPC counts in PAD and DM observed disparate results, which can be due to a lack of consensus on precise EPC immunotype used in the different studies. Nevertheless, the results of EPC-based autologous cell therapy (ACT) are promising. In addition, EPCs have been shown to bean independent predictor of cardiovascular risk and diabetic foot ulcer healing.

• Keywords
• Autologous cell therapy, Diabetes mellitus, Endothelial progenitor cells, Peripheral arterial disease, Vascular repair,
• MeSH
• Cell- and Tissue-Based Therapy methods   MeSH
• Cell Differentiation * MeSH
• Diabetes Mellitus therapy   MeSH
• Endothelial Progenitor Cells cytology   MeSH
• Cells, Cultured MeSH
• Humans MeSH
• Peripheral Arterial Disease therapy   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH