Identification of Prognostic Biomarkers of Adipose-Derived Stem Cells Treatment in Non-healing Vascular Leg Ulcers

医学 金标准(测试) 伤口愈合 川地34 干细胞 脂肪组织 CD146号 内科学 外科 病理 遗传学 生物
作者
Maria Grazia Sibilla,I Zollino,Diana Campioni,Mirko Tessari,Anna Maria Malagoni,Paolo Zamboni
出处
期刊:European Journal of Vascular and Endovascular Surgery [Elsevier BV]
卷期号:58 (6): e407-e408
标识
DOI:10.1016/j.ejvs.2019.06.1049
摘要

Introduction - Autologous adipose tissue-derived stem cells (ASCs) has shown great potential in wound healing for patients not responder to gold standard tratment1-2. However, with easier isolation and better availability ASCs have sparked great clinical and research interest 3. The aim of our study is to identify biomarkers predictive of successful cell treatment in non healing vascular leg ulcers (VLU) using a reproducible technical approach verified in parallel with a deep lab cell characterization. Methods - From an initial cohort of 38 patients, 16 patients affected by non healing VLUs were randomized respectively to gold standard treatment (control arm,5 men 3 women) and to gold standard treatment plus ASCs (experimental arm, 5 men 3 women) sampling according to Coleman's technique4. The sample was centrifuged at 1300 r / min for 3 minutes and injected with an 18 G needle into the edges and into the bed of ulcer. A sample of lipoaspirate was sent simultaneously to the laboratory where it was appropriately treated for FVS extraction5. The cells are incubated with different monoclonal antibodies in order to quantify and characterize the different stem cells present (CD45-CD34 +, CD34 + CD146 +/- etc.). The next step involved the evaluation of cellular clonogenicity to estimate in vitro the number of aggregated fibroblasts (Unit Forming Colonies, CFU-F). The different immunophenotypical and functional characteristic of the harvested ASCs were correlated with clinical outcomes respectively: healing time, pain measured by NRS scale, Margolix index (MI)6, complete healing. Results - No major adverse events were recorded. The healing process was significantly faster by applying ASCs, 17.5± 7.0 weeks vs 24.5 ± 4.9 weeks recorded in the control arm (p<0.036). NRS dropped after the first week to 2.7 ± 2.0 in the experimental arm vs 6.6 ± 3.0, in the controls (p < 0.01). The MI was not significantly different between arms. Very interestingly we found a strong reverse correlation between the % of CD34+/CD45- cells respectively with the healing time (r= -0.894, p<0.041) and NRS (r=-0.934, p<0.020). Moreover, the in vitro expanded non hematopoietic progenitor (expressed as a N° of CFU-F) present an inverted correlation with the healing time (r=-0.868, p<0.057) while a significant correlation with NRS (r=-0.883, p<0.047) (Fig.1). There was also a positive correlation between the MI and the % of the CD34+ cells (r = 0.94 p < 0.005). The relationship between the MI and % of CFU-F is significantly associated (r=0.97 p < 0.002), as is also the correlation between MI with the total number of calculated CFU-F reinfused (r=0.98 p < 0.002). Finally, the number of pericytes described as the % of CD146+/CD271-CD45 low cells correlate significantly with the MI (r = 0.98 p < 0.002). Conclusion - The percentage % of CD34+/CD45- cells seems a predictive biomarker of successful ASCs treatment in these patients. References1.Galipeau J, Krampera M, Barrett J, Dazzi F, Deans RJ, Debruijn J, et al. International Society for Cellular Therapy perspective on immune functional assays for mesenchymal stromal cells as potency release criterion for advanced phase clinical trials. Cytotherapy 2016;18(2):151-9.2.Sousa BR, Parreira RC, Fonseca EA, Amaya MJ, Tonelli FMP, Lacerda SMSN, et al. Human adult stem cells from diverse origins: an overview from multiparametric immunophenotyping to clinical application. Cytometry Part A 2014;85(1):43-77.3.Gimble JM, Bunnell BA, Guilak F. Hum an adipose-derived cells: an update on the transition to clinical translation. Regen Med 2012;7(2):225-35.4.Zollino I, Zuolo M, Gianesini S, Pedriali M, Sibilla MG, Tessari M, et al. Autologous adipose-derived stem cells: basic science, technique, and rationale for application in ulcer and wound healing. Phlebology 2017;32(3):160-71.5.Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, Katz AJ, et al. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng 2001;7(2):211-28.6.Kantor J, Margolis DJ. A multicentre study of percentage change in venous leg ulcer area as a prognostic index of healing at 24 weeks. Br J Dermatol 2000;142(5):960-4.
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