Autologous CD34+ cell transplantation promotes angiogenesis in older adult patients with atherosclerotic ischemia: study protocol for a prospective, single-center, open-label, randomized controlled clinical trial

doi:10.3969/j.issn.2095-4344.2017.13.006

Abstract

Abstract:

BACKGROUND: The main clinical manifestation of senile arteriosclerosis obliterans is lower limb ischemia, which is currently difficult to treat. One method is by autologous stem cell transplantation into the muscles of ischemic limbs to improve the formation of new capillaries and restore lower limb blood flow. Endothelial progenitor cell marker CD34⁺ cell transplantation has been shown to promote angiogenesis in ischemic limbs. Therefore, we propose that peripheral blood autologous CD34⁺ cell transplantation in older adult patients with atherosclerotic ischemia could effectively promote angiogenesis.
OBJECTIVE: To assume that peripheral blood autologous CD34+ cell transplantation in the elderly with atherosclerotic ischemia could effectively promote angiogenesis.
METHODS: This is a prospective, single-center, open-label, randomized, and controlled clinical trial that will be completed at the Qingdao No. 9 People’s Hospital, China. Twenty older adult patients with atherosclerotic lower limb ischemia will be randomized into two groups. In the cell transplantation group (n=10), peripheral blood CD34⁺ cells transfected with vascular endothelial growth factor 165 (VEGF165) gene will be intramuscularly transplanted into the ischemic limbs in older adult patients with atherosclerotic lower limb ischemia. In the control group (n=10), normal saline will be intramuscularly injected into the ischemic limbs. All patients will be followed up for 6 months. The primary outcome will be ankle-brachial indices before and 6 months after transplantation to assess lower limb ischemia in both groups. The secondary outcomes will be the number of microvessels in the lower limb muscles before and 6 months after transplantation, the morphology of new blood vessels revealed by CT angiography, the number of VEGF-immunoreactive cells 6 months after transplantation and the incidence of adverse reactions. The trial was registered at the ClinicalTrials.gov (identifier: NCT03098771), and the study protocol was approved by the Ethics Committee of Qingdao No. 9 People’s Hospital of China. All protocols will be in accordance with Declaration of Helsinki, formulated by the World Medical Association. All patients will be informed of study protocols and provide a written informed consent prior to the beginning of the trial.
DISCUSSION: This trial will begin in January 2018 and finish in December 2019. We aim to quantify the effects of VEGF165 gene-modified CD34⁺ cell transplantation in the treatment of older adult patients with atherosclerotic ischemia to develop a new effective treatment of lower limb ischemia.

中国组织工程研究杂志出版内容重点：干细胞；骨髓干细胞；造血干细胞；脂肪干细胞；肿瘤干细胞；胚胎干细胞；脐带脐血干细胞；干细胞诱导；干细胞分化；组织工程

Key words: Stem Cells, Vascular Endothelial Growth Factors, Tissue Engineering

CLC Number:

R394.2

Zhou Chen-hong, Xu Li-li, Hao Xiu-xian, Sun Xiao-juan, Guo Ming-jin, Liu Bing. Autologous CD34⁺ cell transplantation promotes angiogenesis in older adult patients with atherosclerotic ischemia: study protocol for a prospective, single-center, open-label, randomized controlled clinical trial[J]. Chinese Journal of Tissue Engineering Research, 2017, 21(13): 1998-2002.

Figures/Tables 1

References

[1] Rodrigues CG, Plentz RD, Dipp T, et al. VEGF 165 gene therapy for patients with refractory angina: mobilization of endothelial progenitor cells. Arq Bras Cardiol. 2013;101:149-153.

[2] Cangiano E, Cavazza C, Campo G, et al. Different clinical models of CD34+ cells mobilization in patients with cardiovascular disease. J Thromb Thrombolysis. 2011;32: 1-8.

[3] Sasaki KI, Chibana H, Ueno T, et al. Successful endovascular treatment of aortoiliac bifurcation stenosis using an empirically based T and protrude-stenting with self- and balloon- expandable stents. Kurume Med J. 2017. doi: 10.2739/kurumemedj.MS6300010.

[4] Zhuang JM, Li X, Li TR, et al. Randomized controlled trial to superficial femoral artery recanalization for lower extremity arteriosclerosis obliterans. Beijing Da Xue Xue Bao Yi Xue Ban. 2017;49:153-157.

[5] Japanese Society for Vascular Surgery JCLIMB Committee; NCD JCLIMB Analytical Team. 2014 JAPAN Critical Limb Ischemia Database (JCLIMB) Annual Report. Ann Vasc Dis. 2016;9:374-391.

[6] Balbi C, Piccoli M, Barile L, et al. First Characterization of human amniotic fluid stem cell extracellular vesicles as a powerful paracrine tool endowed with regenerative potential. Stem Cells Trans Med. 2017. doi: 10.1002/sctm.16-0297.

[7] Manjunathan R, Ragunathan M. In ovo administration of human recombinant leptin shows dose dependent angiogenic effect on chicken chorioallantoic membrane. Biol Res. 2015;48:29.

[8] Park IS, Chung PS, Ahn JC. Enhancement of Ischemic Wound Healing by Spheroid Grafting of Human Adipose-Derived Stem Cells Treated with Low-Level Light Irradiation. PLoS One. 2015;10:e0122776.

[9] Zhao P, Chen Y, Yue Z, et al. Bone marrow mesenchymal stem cells regulate stemness of multiple myeloma cell lines via BTK signaling pathway. Leuk Res. 2017;57:20-26.

[10] Fujisaki J, Wu J, Carlson AL, et al. In vivo imaging of Treg cells providing immune privilege to the haematopoietic stem-cell niche. Nature. 2011;474:216-219.

[11] Orrico C, Pasquinelli G, Foroni L, et al. Dysfunctional vasa vasorum in diabetic peripheral artery obstructive disease with critical lower limb ischaemia. Eur J Vasc Endovasc Surg. 2010;40:365-374.

[12] Tan K, Lessieur E, Cutler A, et al. Impaired function of circulating CD34(+) CD45(-) cells in patients with proliferative diabetic retinopathy. Exp Eye Res. 2010;91:229-237.

[13] Taguchi A. Cell-based therapy for patients with vascular dementia. Psychogeriatrics. 2011;11:113-115.

[14] Yoo CH, Na HJ, Lee DS, et al. Endothelial progenitor cells from human dental pulp-derived iPS cells as a therapeutic target for ischemic vascular diseases. Biomaterials. 2013; 34:8149-8160.

[15] Li CH, Chen Y, Zhang CH, et al. Observation of clinical efficacy of rt-PA intravenous thrombolytic treatment for patients combined with grade 0-1 diabetic foot by Wagner classification and acute ischemic stroke. Eur Rev Med Pharmacol Sci. 2016;20:5168-5173.

[16] Zhang H, Lei C, Zhang TY, et al. Transcutaneous electri¬cal acupoint stimulation with different acupoint combinations on opioid consumption in patients undergoing off-pump coronary artery bypass grafting: study protocol for a randomized double-blind controlled trial. Clin Transl Degener Dis. 2016;1(1):17-24.

[17] Wang Y (2016) Chinese medicine packet plus wax therapy for periarthritis of the shoulder: study protocol for a multi-center randomized controlled trial. Clin Transl Degener Dis. 2016; 1(1): 25-31.

[18] Ma N, Peng J, Guo QY (2016) Local administration of enriched mononuclear cells, platelets and zoledronic acid for preventing collapse of the femoral head in the early stage of osteonecrosis: study protocol for a prospective randomized parallel-controlled clinical trial. Clin Transl Degener Dis. 2016;1(1):32-37.

[19] 马海涛,周涛,邱文淼,等.自体骨髓干细胞移植联合当归活血汤治疗糖尿病足[J].中国组织工程研究,2015,19(50):8139-8143.