干细胞治疗糖尿病足创面的研究进展

林志琥; 王君; 梁尊鸿; 潘云川

doi:10.3760/cma.j.cn501120-20210828-00292

干细胞治疗糖尿病足创面的研究进展

doi: 10.3760/cma.j.cn501120-20210828-00292

海南省人民医院海南医学院附属海南医院烧伤与皮肤修复外科，海口　　570311

基金项目:

海南省院士创新平台科研专项 ysptzx202028

海南省基础与应用基础研究计划 821RC676

详细信息

通讯作者:
潘云川，Email：pychuan@qq.com

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出版历程
- 收稿日期: 2021-08-28

Research advances on stem cell therapy for diabetic foot wounds

Department of Burn and Skin Repair, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou 570311, China

Funds:

The Specific Research Fund of the Innovation Platform for Academicians of Hainan Province ysptzx202028

Basic and Applied Basic Research Programs of Hainan Province of China 821RC676

More Information

Corresponding author: Pan Yunchuan, Email: pychuan@qq.com

摘要

摘要:
糖尿病足创面修复是临床棘手问题，由于机体局部组织损毁且再生障碍，通过血管、神经营养修复创面的途径受损，多种细胞因子紊乱等多因素影响，传统治疗方法往往难以取得良好治疗效果。干细胞是一类具有多向分化潜能的细胞，且具有免疫调节、旁分泌等功能，有助于全方位修复创面，目前在糖尿病足创面中极具应用前景。但由于干细胞治疗相关参数仍然处于探索阶段，尚无标准化数据。本文综述了近6年来干细胞在糖尿病足创面治疗研究中的应用，重点对研究中的干细胞类型和来源，供体年龄、性别对干细胞的影响，给药方式，移植存活率，安全性等内容进行总结和分析，为干细胞进一步应用于临床上糖尿病足创面的治疗提供参考。
- 干细胞 /
- 糖尿病足 /
- 给药途径 /
- 干细胞剂量 /
- 安全性
Abstract:
Diabetic foot wound repair is a challenging issue in clinical practice. Due to the influence of multiple factors including the damage and regeneration failure of local tissue, the impaired pathways of wound repairing through blood vessels and nerve nutrition, and disorders of a variety of cellular factors, traditional treatment methods are often difficult to achieve good therapeutic effects. Stem cells are a type of cells with potentials of multidirectional differentiation, which also possess functions such as regulating immunity and paracrine to facilitate the comprehensive wound repair, so they have promising application prospect at present for the treatment of diabetic foot wounds. Because the relevant parameters of stem cell treatment are in the exploratory phase, there were no standardized data. This paper reviews the application of stem cells in the research of diabetic foot wound treatment over the past 6 years, analyzing and summarizing the contents in focused aspects including the types and sources of stem cells, effects of donor age and gender on stem cells, mode of administration, transplantation survival rate and safety, which may provide a reference for further application of stem cells in the clinical treatment of diabetic foot wound.
- Stem cells /
- Diabetic foot /
- Route of administration /
- Stem cell dose /
- Safety
所有作者均声明不存在利益冲突

大面积烧伤可诱发复杂的免疫反应，严重影响患者预后。中性粒细胞作为天然免疫的重要效应细胞，其在患者烧伤休克阶段的功能作用尚不十分清楚。该研究观察到，烧伤休克患者血液循环中的中性粒细胞计数和百分比（中性粒细胞占白细胞总数的比值）明显增加，进一步采用免疫荧光成像技术在烧伤患者或动物模型中观察到中性粒细胞的细胞核存在左移现象。通过琼脂糖迁移模型评估中性粒细胞的趋化功能，显示其趋化能力在烧伤患者早期即出现明显下降，这种下降与细菌内毒素激活P2RX1介导中性粒细胞趋化停止信号有关。进一步研究观察到，从烧伤休克患者血液中分离出来的中性粒细胞释放了更多的抗菌蛋白，但抗菌蛋白并非是通过中性粒细胞胞外诱捕网（NET）途径产生的，而主要是通过中性粒细胞脱颗粒的胞吐作用来实现的。同时，烧伤患者中性粒细胞通过产生活性氧自由基和NET进行抗菌的能力明显减弱。此外，中性粒细胞释放肝素结合蛋白及中性粒细胞表面P2RX1表达增加促进了血管渗漏的发生。因此，针对以中性粒细胞为代表的免疫系统早期干预和调节将有利于重度烧伤患者的治疗。

刘双庆，编译自《Burns》,2021,47(8):1851-1862；姚咏明，审校

·撤稿声明·

撤稿：严重爆炸致烧伤患者感染病原微生物的特征及宏基因组学第二代测序技术在病原微生物检测中的应用（中华烧伤杂志，2021，37(10)：946-952）

《中华烧伤与创面修复杂志》（原《中华烧伤杂志》）编辑部：

我们在原《中华烧伤杂志》2021年第37卷第10期刊发的“严重爆炸致烧伤患者感染病原微生物的特征及宏基因组学第二代测序技术在病原微生物检测中的应用”^[1]一文在发表过程中未经其中某一作者同意却将其进行署名，造成异议，特申请从贵刊撤稿，并就由此带来的不便向编辑部致歉。

罗汝斌黄曼胡行张嵘韩春茂

2021年12月10日

［1］罗汝斌，黄曼，胡行，等.严重爆炸致烧伤患者感染病原微生物的特征及宏基因组学第二代测序技术在病原微生物检测中的应用[J].中华烧伤杂志, 2021, 37(10): 946-952.DOI:10.3760/cma.j.cn501120-20201017-00440.

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参考文献(47)

[1]	ReardonR, SimringD, KimB, et al. The diabetic foot ulcer[J]. Aust J Gen Pract, 2020,49(5):250-255. DOI: 10.31128/AJGP-11-19-5161.
[2]	HeubleinH, BaderA, GiriS. Preclinical and clinical evidence for stem cell therapies as treatment for diabetic wounds[J]. Drug Discov Today, 2015,20(6):703-717. DOI: 10.1016/j.drudis.2015.01.005.
[3]	YanJX, LiangJJ, CaoYX, et al. Efficacy of topical and systemic transplantation of mesenchymal stem cells in a rat model of diabetic ischemic wounds[J]. Stem Cell Res Ther, 2021,12(1):220. DOI: 10.1186/s13287-021-02288-8.
[4]	WangP, TheocharidisG, VlachosIS, et al. Exosomes derived from epidermal stem cells improve diabetic wound healing[J/OL]. J Invest Dermatol, 2022:S0022-202X(22)00119-1(2022-02-15)[2022-02-23]. https://pubmed.ncbi.nlm.nih.gov/35181300/.DOI: 10.1016/j.jid.2022.01.030. [published online ahead of print].
[5]	ZhaoLL, GuoZ, ChenK, et al. Combined transplantation of mesenchymal stem cells and endothelial colony-forming cells accelerates refractory diabetic foot ulcer healing[J]. Stem Cells Int,2020,2020:8863649. DOI: 10.1155/2020/8863649.
[6]	杜俊文, 吴韬, 张坤, 等. 脐带间充质干细胞联合骨髓干细胞治疗下肢缺血[J]. 中国组织工程研究,2017,21(1):82-86. DOI: 10.3969/j.issn.2095-4344.2017.01.015.
[7]	LuDB, JiangYZ, DengWQ, et al. Long-term outcomes of BMMSC compared with BMMNC for treatment of critical limb ischemia and foot ulcer in patients with diabetes[J]. Cell Transplant,2019,28(5):645-652. DOI: 10.1177/0963689719835177.
[8]	WuQN, LeiXT, ChenL, et al. Autologous platelet-rich gel combined with in vitro amplification of bone marrow mesenchymal stem cell transplantation to treat the diabetic foot ulcer: a case report[J]. Ann Transl Med,2018,6(15):307. DOI: 10.21037/atm.2018.07.12.
[9]	KočíZ, TurnovcováK, DubskýM, et al. Characterization of human adipose tissue-derived stromal cells isolated from diabetic patient's distal limbs with critical ischemia[J]. Cell Biochem Funct,2014,32(7):597-604. DOI: 10.1002/cbf.3056.
[10]	YangPH, ShenWB, ReeceEA, et al. High glucose suppresses embryonic stem cell differentiation into neural lineage cells[J]. Biochem Biophys Res Commun,2016,472(2):306-312. DOI: 10.1016/j.bbrc.2016.02.117.
[11]	Mohamed-AhmedS, YassinMA, RashadA, et al. Comparison of bone regenerative capacity of donor-matched human adipose-derived and bone marrow mesenchymal stem cells[J]. Cell Tissue Res,2021,383(3):1061-1075. DOI: 10.1007/s00441-020-03315-5.
[12]	PillK, MelkeJ, MühlederS, et al. Microvascular networks from endothelial cells and mesenchymal stromal cells from adipose tissue and bone marrow: a comparison[J]. Front Bioeng Biotechnol,2018,6:156. DOI: 10.3389/fbioe.2018.00156.
[13]	SukhoP, HesselinkJW, KopsN, et al. Human mesenchymal stromal cell sheets induce macrophages predominantly to an anti-inflammatory phenotype[J]. Stem Cells Dev,2018,27(13):922-934. DOI: 10.1089/scd.2017.0275.
[14]	ShiRF, LianWS, JinYP, et al. Role and effect of vein-transplanted human umbilical cord mesenchymal stem cells in the repair of diabetic foot ulcers in rats[J]. Acta Biochim Biophys Sin (Shanghai),2020,52(6):620-630. DOI: 10.1093/abbs/gmaa039.
[15]	BakshD, YaoR, TuanRS. Comparison of proliferative and multilineage differentiation potential of human mesenchymal stem cells derived from umbilical cord and bone marrow[J]. Stem Cells,2007,25(6):1384-1392. DOI: 10.1634/stemcells.2006-0709.
[16]	VidalMA, WalkerNJ, NapoliE, et al. Evaluation of senescence in mesenchymal stem cells isolated from equine bone marrow, adipose tissue, and umbilical cord tissue[J]. Stem Cells Dev,2012,21(2):273-283. DOI: 10.1089/scd.2010.0589.
[17]	KernS, EichlerH, StoeveJ, et al. Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue[J]. Stem Cells,2006,24(5):1294-1301. DOI: 10.1634/stemcells.2005-0342.
[18]	ZeddouM, RelicB, MalaiseMG. Umbilical cord fibroblasts: could they be considered as mesenchymal stem cells?[J]. World J Stem Cells,2014,6(3):367-370. DOI: 10.1634/stemcells.2005-0342.
[19]	ScatenaA, PetruzziP, MaioliF, et al. Autologous peripheral blood mononuclear cells for limb salvage in diabetic foot patients with no-option critical limb ischemia[J]. J Clin Med,2021,10(10):2213. DOI: 10.3390/jcm10102213.
[20]	GoreckaJ, GaoXX, FereydooniA, et al. Induced pluripotent stem cell-derived smooth muscle cells increase angiogenesis and accelerate diabetic wound healing[J]. Regen Med,2020,15(2):1277-1293. DOI: 10.2217/rme-2019-0086.
[21]	SatoH, EbisawaK, TakanariK, et al. Skin-derived precursor cells promote wound healing in diabetic mice[J]. Ann Plast Surg,2015,74(1):114-120. DOI: 10.1097/SAP.0000000000000342.
[22]	ChoudheryMS, BadowskiM, MuiseA, et al. Donor age negatively impacts adipose tissue-derived mesenchymal stem cell expansion and differentiation[J]. J Transl Med,2014,12:8. DOI: 10.1186/1479-5876-12-8.
[23]	BeaneOS, FonsecaVC, CooperLL, et al. Impact of aging on the regenerative properties of bone marrow-, muscle-, and adipose-derived mesenchymal stem/stromal cells[J]. PLoS One,2014,9(12):e115963. DOI: 10.1371/journal.pone.0115963.
[24]	SiegelG, KlubaT, Hermanutz-KleinU, et al. Phenotype, donor age and gender affect function of human bone marrow-derived mesenchymal stromal cells[J]. BMC Med,2013,11:146. DOI: 10.1186/1741-7015-11-146.
[25]	YanJX, LiangJJ, CaoYX, et al. Efficacy of topical and systemic transplantation of mesenchymal stem cells in a rat model of diabetic ischemic wounds[J]. Stem Cell Res Ther,2021,12(1):220. DOI: 10.1186/s13287-021-02288-8.
[26]	Sanchez-DiazM, Quiñones-VicoMI, Sanabria de la Torre R, et al. Biodistribution of mesenchymal stromal cells after administration in animal models and humans: a systematic review[J]. J Clin Med,2021,10(13):2925. DOI: 10.3390/jcm10132925.
[27]	LeeRH, SeoMJ, PulinAA, et al. The CD34-like protein PODXL and alpha6-integrin (CD49f) identify early progenitor MSCs with increased clonogenicity and migration to infarcted heart in mice[J]. Blood,2009,113(4):816-826. DOI: 10.1182/blood-2007-12-128702.
[28]	AmerMH, FRAJRose, ShakesheffKM, et al. A biomaterials approach to influence stem cell fate in injectable cell-based therapies[J]. Stem Cell Res Ther,2018,9(1):39. DOI: 10.1186/s13287-018-0789-1.
[29]	KatoY, IwataT, MorikawaS, et al. Allogeneic transplantation of an adipose-derived stem cell sheet combined with artificial skin accelerates wound healing in a rat wound model of type 2 diabetes and obesity[J]. Diabetes,2015,64(8):2723-2734. DOI: 10.2337/db14-1133.
[30]	HuangS, YaoB, XieJF, et al. 3D bioprinted extracellular matrix mimics facilitate directed differentiation of epithelial progenitors for sweat gland regeneration[J]. Acta Biomater,2016,32:170-177. DOI: 10.1016/j.actbio.2015.12.039.
[31]	WangJ, ZengXX, CaiW, et al. Safety and efficacy of placenta-derived mesenchymal stem cell treatment for diabetic patients with critical limb ischemia: a pilot study[J]. Exp Clin Endocrinol Diabetes,2021,129(7):542-548.DOI: 10.1055/a-0978-4972.
[32]	YangHY, FierroF, SoM, et al. Combination product of dermal matrix, human mesenchymal stem cells, and timolol promotes diabetic wound healing in mice[J]. Stem Cells Transl Med,2020,9(11):1353-1364. DOI: 10.1002/sctm.19-0380.
[33]	SeoE, LimJS, JunJB, et al. Exendin-4 in combination with adipose-derived stem cells promotes angiogenesis and improves diabetic wound healing[J]. J Transl Med,2017,15(1):35. DOI: 10.1186/s12967-017-1145-4.
[34]	De GregorioC, ContadorD, DíazD, et al. Human adipose-derived mesenchymal stem cell-conditioned medium ameliorates polyneuropathy and foot ulceration in diabetic BKS db/db mice[J]. Stem Cell Res Ther,2020,11(1):168. DOI: 10.1186/s13287-020-01680-0.
[35]	ChokesuwattanaskulS, SukpatS, DuangpatraJ, et al. High dose oral vitamin C and mesenchymal stem cells aid wound healing in a diabetic mouse model[J]. J Wound Care,2018,27(5):334-339. DOI: 10.12968/jowc.2018.27.5.334.
[36]	ZhuLY, WangGX, FischbachS, et al. Suppression of microRNA-205-5p in human mesenchymal stem cells improves their therapeutic potential in treating diabetic foot disease[J]. Oncotarget,2017,8(32):52294-52303. DOI: 10.18632/oncotarget.17012.
[37]	ShawkyLM, El BanaEA, MorsiAA. Stem cells and metformin synergistically promote healing in experimentally induced cutaneous wound injury in diabetic rats[J]. Folia Histochem Cytobiol,2019,57(3):127-138. DOI: 10.5603/FHC.a2019.0014.
[38]	AriyantiAD, ZhangJQ, MarcelinaO, et al. Salidroside- pretreated mesenchymal stem cells enhance diabetic wound healing by promoting paracrine function and survival of mesenchymal stem cells under hyperglycemia[J]. Stem Cells Transl Med,2019,8(4):404-414. DOI: 10.1002/sctm.18-0143.
[39]	MoradiA, ZareF, MostafaviniaA, et al. Photobiomodulation plus adipose-derived stem cells improve healing of ischemic infected wounds in type 2 diabetic rats[J]. Sci Rep,2020,10(1):1206. DOI: 10.1038/s41598-020-58099-z.
[40]	ShehadahA, ChenJL, PalA, et al. Human placenta-derived adherent cell treatment of experimental stroke promotes functional recovery after stroke in young adult and older rats[J]. PLoS One,2014,9(1):e86621. DOI: 10.1371/journal.pone.0086621.
[41]	CovaL, ArmenteroMT, ZennaroE, et al. Multiple neurogenic and neurorescue effects of human mesenchymal stem cell after transplantation in an experimental model of Parkinson's disease[J]. Brain Res, 2010,1311:12-27. DOI: 10.1016/j.brainres.2009.11.041.
[42]	LiangL, LiZJ, MaT,et al. Transplantation of human placenta-derived mesenchymal stem cells alleviates critical limb ischemia in diabetic nude rats[J]. Cell Transplant,2017,26(1):45-61. DOI: 10.3727/096368916X692726.
[43]	BaiXW, YanYS, ColemanM, et al. Tracking long-term survival of intramyocardially delivered human adipose tissue-derived stem cells using bioluminescence imaging[J]. Mol Imaging Biol,2011,13(4):633-645. DOI: 10.1007/s11307-010-0392-z.
[44]	ShafiqM, JungY, KimSH. Insight on stem cell preconditioning and instructive biomaterials to enhance cell adhesion, retention, and engraftment for tissue repair[J]. Biomaterials,2016,90:85-115. DOI: 10.1016/j.biomaterials.2016.03.020.
[45]	HuCX, LiLJ. Preconditioning influences mesenchymal stem cell properties in vitro and in vivo[J]. J Cell Mol Med,2018,22(3):1428-1442. DOI: 10.1111/jcmm.13492.
[46]	SkylerJS, FonsecaVA, SegalKR, et al. Allogeneic mesenchymal precursor cells in type 2 diabetes: a randomized, placebo-controlled, dose-escalation safety and tolerability pilot study[J]. Diabetes Care,2015,38(9):1742-1749. DOI: 10.2337/dc14-2830.
[47]	YuJL, ChanS, FungMK, et al. Mesenchymal stem cells accelerated growth and metastasis of neuroblastoma and preferentially homed towards both primary and metastatic loci in orthotopic neuroblastoma model[J]. BMC Cancer, 2021,21(1):393. DOI: 10.1186/s12885-021-08090-2.