Effect and mechanism of human adipose-derived stem cell exosomes on diabetic peripheral neuropathy

Cao Tao; Hao Tong; Xiao Dan; Zhang Weifeng; Ji Peng; Jia Yanhui; Wang Jing; Wang Xujie; Guan Hao; Tao Ke

doi:10.3760/cma.j.cn501225-20231207-00230

Volume 40 Issue 3

Mar. 2024

Turn off MathJax

Article Contents

Abstract

References

Article Navigation > CHINESE JOURNAL OF BURNS AND WOUNDS > 2024 > 40(3): 240-248

Cao T,Hao T,Xiao D,et al.Effect and mechanism of human adipose-derived stem cell exosomes on diabetic peripheral neuropathy[J].Chin J Burns Wounds,2024,40(3):240-248.DOI: 10.3760/cma.j.cn501225-20231207-00230.

Citation:

PDF( 4668 KB)

Effect and mechanism of human adipose-derived stem cell exosomes on diabetic peripheral neuropathy

doi: 10.3760/cma.j.cn501225-20231207-00230

1.
Department of Burns and Cutaneous Surgery, Burn Center of PLA, the First Affiliated Hospital of Air Force Medical University, Xi'an 710032, China
2.
College of Life Sciences, Shaanxi Normal University, Xi'an 710032, China
3.
Department of Emergency, PLA 63600 Army Hospital, Jiuquan 712750, China
4.
Department of Wound Repair, Center for Wound Repair and Regenerative Medicine, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, China

Funds:

General Program of National Natural Science Foundation of China 82272269

More Information

Corresponding author: Tao Ke, Email: tao-ke2001@163.com
Received Date: 2023-12-07

Abstract

Abstract

Objective To investigate the changes of artemin protein expression in diabetic peripheral neuropathy (DPN) and to explore the regulatory effect of human adipose-derived stem cell (ADSC) exosomes on the change of artemin protein expression. Methods This research was a prospective observational clinical research combined with experimental research. Thirteen DPN patients (9 males and 4 females, aged 32 to 68 years) who were admitted to the First Affiliated Hospital of Air Force Medical University (hereinafter referred to as our hospital) from May 2022 to October 2023 and met the inclusion criteria were selected as DPN group, and 5 non-diabetes patients (4 males and 1 female, aged 29 to 61 years) who were admitted to our hospital in the same period of time and met the inclusion criteria were selected as control group. The toe nerve or sural nerve tissue in the abandoned tissue after debridement or amputation of patients in the two groups was collected. The pathological changes of nerve tissue were observed after hematoxylin-eosin staining; the protein expressions of S100β and artemin in nerve tissue were observed after immunofluorescence staining, and the artemin protein expression was quantified; the protein and mRNA expressions of artemin were detected by Western blotting and real-time fluorescent quantitative reverse transcription polymerase chain reaction, respectively (the sample number in DPN group and control group was 13 and 5, respectively). Twelve male C57BL/6 mice aged 3 to 5 days were collected to isolate Schwann cells, and the cells were divided into conventional culture group cultured routinely, high glucose alone group (cultured with high concentration of glucose solution only), and high glucose+exosome group (cultured with high concentration of glucose solution and extracted human ADSC exosomes). After 24 hours of culture, the cell proliferation activity was detected by cell counting kit 8 ( n=6). After 48 hours of culture, the protein expression of artemin was detected by Western blotting ( n=3). Results Compared with those in control group, the neural supporting cells decreased and the inflammatory cells increased in the nerve tissue of patients in DPN group, showing typical manifestations of nerve injury. Immunofluorescence staining showed that compared with those in control group, the nuclei was more, and the protein expression of S100β was lower in nerve tissue of patients in DPN group. The protein expression of artemin in nerve tissue of patients in DPN group was 71±31, which was significantly lower than 1 729±62 in control group ( t=76.92, P<0.05). Western blotting detection showed that the protein expression of artemin in nerve tissue of patients in DPN group was 0.74±0.08, which was significantly lower than 0.97±0.06 in control group ( t=5.49, P<0.05). The artemin mRNA expression in nerve tissue of patients in DPN group was significantly lower than that in control group ( t=7.65, P<0.05). After 24 hours of culture, compared with that in conventional culture group, the proliferation activities of Schwann cells in high glucose alone group and high glucose+exosome group were significantly decreased ( P<0.05); compared with that in high glucose alone group, the proliferation activity of Schwann cells in high glucose+exosome group was significantly increased ( P<0.05). After 48 hours of culture, compared with those in conventional culture group, the protein expressions of artemin of Schwann cells in high glucose alone group and high glucose+exosome group were significantly decreased ( P<0.05); compared with that in high glucose alone group, the protein expression of artemin of Schwann cells in high glucose+exosome group was significantly increased ( P<0.05). Conclusions The protein expression of artemin in nerve tissue of DPN patients is lower than that in normal nerve tissue, which may be related to the reduction of proliferation activity of Schwann cells by high glucose. Human ADSC exosomes may improve the proliferation activity of Schwann cells by increasing artemin protein expression, thereby delaying the progression of DPN.
- Diabetic neuropathies,
- Exosomes,
- Cell proliferation,
- Schwann cells,
- Artemin,
- Adipose-derived stem cells

FullText(HTML)

References(38)

References

[1]	RehmanZU.Saving limbs in diabetics: challenges and opportunities[J].J Coll Physicians Surg Pak,2020,30(10):1003-1004.DOI: 10.29271/jcpsp.2020.10.1003.
[2]	LowLL, KwanYH, KoMSM, et al. Epidemiologic characteristics of multimorbidity and sociodemographic factors associated with multimorbidity in a rapidly aging Asian country[J]. JAMA Netw Open, 2019,2(11):e1915245. DOI: 10.1001/jamanetworkopen.2019.15245.
[3]	《多学科合作下糖尿病足防治专家共识(2020版)》编写组.多学科合作下糖尿病足防治专家共识(2020版)全版[J].中华烧伤杂志,2020,36(8):E01-E52.DOI: 10.3760/cma.j.cn501120-20200217-01000.
[4]	Sable-MoritaS,OkuraM,TanikawaT,et al.Associations between diabetes-related foot disease, diabetes, and age-related complications in older patients[J].Eur Geriatr Med,2021,12(5):1003-1009.DOI: 10.1007/s41999-021-00491-7.
[5]	ElafrosMA,AndersenH,BennettDL,et al.Towards prevention of diabetic peripheral neuropathy: clinical presentation, pathogenesis, and new treatments[J].Lancet Neurol,2022,21(10):922-936.DOI: 10.1016/S1474-4422(22)00188-0.
[6]	EidSA,RumoraAE,BeirowskiB,et al.New perspectives in diabetic neuropathy[J].Neuron,2023,111(17):2623-2641.DOI: 10.1016/j.neuron.2023.05.003.
[7]	YinK,QiaoT,ZhangY,et al.Unraveling shared risk factors for diabetic foot ulcer: a comprehensive Mendelian randomization analysis[J].BMJ Open Diabetes Res Care,2023,11(6):e003523. DOI: 10.1136/bmjdrc-2023-003523.
[8]	SenCK,RoyS,KhannaS.Diabetic peripheral neuropathy associated with foot ulcer: one of a kind[J/OL].Antioxid Redox Signal,2023(2023-01-25)[2023-12-07]. https://pubmed.ncbi.nlm.nih.gov/35850520/.DOI:10.1089/ars.2022.0093.[published online ahead of print].
[9]	ChenD,WangM,ShangX,et al.Development and validation of an incidence risk prediction model for early foot ulcer in diabetes based on a high evidence systematic review and meta-analysis[J].Diabetes Res Clin Pract,2021,180:109040.DOI: 10.1016/j.diabres.2021.109040.
[10]	BhandariR,SharmaA,KuhadA.Novel nanotechnological approaches for targeting dorsal root ganglion (DRG) in mitigating diabetic neuropathic pain (DNP)[J].Front Endocrinol (Lausanne),2022,12:790747.DOI: 10.3389/fendo.2021.790747.
[11]	SloanG, AlamU, SelvarajahD, et al. The treatment of painful diabetic neuropathy [J]. Curr Diabetes Rev, 2022, 18(5): e070721194556. DOI: 10.2174/1573399817666210707112413.
[12]	NoceraG,JacobC.Mechanisms of Schwann cell plasticity involved in peripheral nerve repair after injury[J].Cell Mol Life Sci,2020,77(20):3977-3989.DOI: 10.1007/s00018-020-03516-9.
[13]	Bosch-QueraltM,FledrichR,StassartRM.Schwann cell functions in peripheral nerve development and repair[J].Neurobiol Dis,2023,176:105952.DOI: 10.1016/j.nbd.2022.105952.
[14]	RachanaKS,ManuMS,AdviraoGM.Insulin-induced upregulation of lipoprotein lipase in Schwann cells during diabetic peripheral neuropathy[J].Diabetes Metab Syndr,2018,12(4):525-530.DOI: 10.1016/j.dsx.2018.03.017.
[15]	ZhangX,ZhaoS,YuanQ,et al.TXNIP, a novel key factor to cause Schwann cell dysfunction in diabetic peripheral neuropathy, under the regulation of PI3K/Akt pathway inhibition-induced DNMT1 and DNMT3a overexpression[J].Cell Death Dis,2021,12(7):642.DOI: 10.1038/s41419-021-03930-2.
[16]	ZhuS,LiY,BennettS,et al.The role of glial cell line-derived neurotrophic factor family member artemin in neurological disorders and cancers[J].Cell Prolif,2020,53(7):e12860.DOI: 10.1111/cpr.12860.
[17]	IlievaM, NielsenJ, KorshunovaI, et al. Artemin and an Artemin-derived peptide, artefin, induce neuronal survival, and differentiation through ret and NCAM[J].Front Mol Neurosci, 2019,12:47. DOI: 10.3389/fnmol.2019.00047.
[18]	WangR,RossomandoA,SahDWY,et al.Artemin induced functional recovery and reinnervation after partial nerve injury[J].Pain,2014,155(3):476-484.DOI: 10.1016/j.pain.2013.11.007.
[19]	WongLE, GibsonME, ArnoldHM, et al. Artemin promotes functional long-distance axonal regeneration to the brainstem after dorsal root crush[J]. Proc Natl Acad Sci U S A, 112(19):6170-6175. DOI: 10.1073/pnas.1502057112.
[20]	中华医学会糖尿病学分会,中华医学会感染病学分会,中华医学会组织修复与再生分会.中国糖尿病足防治指南(2019版)(Ⅰ)[J].中华糖尿病杂志,2019,11(2):92-108.DOI: 10.3760/cma.j.issn.1674-5809.2019.02.004.
[21]	ZhangY,BiJ,HuangJ,et al.Exosome: a review of its classification, isolation techniques, storage, diagnostic and targeted therapy applications[J].Int J Nanomedicine,2020,15:6917-6934.DOI: 10.2147/IJN.S264498.
[22]	ShanF,JiQ,SongY,et al.A fast and efficient method for isolating Schwann cells from sciatic nerves of neonatal mice[J].J Neurosci Methods,2022,366:109404.DOI: 10.1016/j.jneumeth.2021.109404.
[23]	LiK,ShiX,LuoM,et al.Taurine protects against myelin damage of sciatic nerve in diabetic peripheral neuropathy rats by controlling apoptosis of Schwann cells via NGF/Akt/GSK3β pathway[J].Exp Cell Res,2019,383(2):111557.DOI: 10.1016/j.yexcr.2019.111557.
[24]	LiuB,XinW,TanJR,et al.Myelin sheath structure and regeneration in peripheral nerve injury repair[J].Proc Natl Acad Sci U S A,2019,116(44):22347-22352.DOI: 10.1073/pnas.1910292116.
[25]	AhmedZ,SuggateEL,BrownER,et al.Schwann cell-derived factor-induced modulation of the NgR/p75NTR/EGFR axis disinhibits axon growth through CNS myelin in vivo and in vitro[J].Brain,2006,129(Pt 6):1517-1533.DOI: 10.1093/brain/awl080.
[26]	HuangL,XiaB,ShiX,et al.Time-restricted release of multiple neurotrophic factors promotes axonal regeneration and functional recovery after peripheral nerve injury[J].FASEB J,2019,33(7):8600-8613.DOI: 10.1096/fj.201802065RR.
[27]	MajdH,AminS,GhazizadehZ,et al.Deriving Schwann cells from hPSCs enables disease modeling and drug discovery for diabetic peripheral neuropathy[J].Cell Stem Cell,2023,30(5):632-647.e10.DOI: 10.1016/j.stem.2023.04.006.
[28]	YuanQ,ZhangX,WeiW,et al.Lycorine improves peripheral nerve function by promoting Schwann cell autophagy via AMPK pathway activation and MMP9 downregulation in diabetic peripheral neuropathy[J].Pharmacol Res,2022,175:105985.DOI: 10.1016/j.phrs.2021.105985.
[29]	BolonB,JingS,AsuncionF,et al.The candidate neuroprotective agent artemin induces autonomic neural dysplasia without preventing peripheral nerve dysfunction[J].Toxicol Pathol,2004,32(3):275-294.DOI: 10.1080/01926230490431475.
[30]	TakakuS,TsukamotoM,NiimiN,et al.Exendin-4 promotes Schwann cell survival/migration and myelination in vitro[J].Int J Mol Sci,2021,22(6):2971.DOI: 10.3390/ijms22062971.
[31]	YinY,QuH,YangQ,et al.Astragaloside Ⅳ alleviates Schwann cell injury in diabetic peripheral neuropathy by regulating microRNA-155-mediated autophagy[J].Phytomedicine,2021,92:153749.DOI: 10.1016/j.phymed.2021.153749.
[32]	FontanaX,HristovaM,Da CostaC,et al.c-Jun in Schwann cells promotes axonal regeneration and motoneuron survival via paracrine signaling[J].J Cell Biol,2012,198(1):127-141.DOI: 10.1083/jcb.201205025.
[33]	de AssisACC,ReisALS,NunesLV,et al.Stem cells and tissue engineering-based therapeutic interventions: promising strategies to improve peripheral nerve regeneration[J].Cell Mol Neurobiol,2023,43(2):433-454.DOI: 10.1007/s10571-022-01199-3.
[34]	RhodeSC,BeierJP,RuhlT.Adipose tissue stem cells in peripheral nerve regeneration-in vitro and in vivo[J].J Neurosci Res,2021,99(2):545-560.DOI: 10.1002/jnr.24738.
[35]	AzamM,GhufranH,ButtH,et al.Curcumin preconditioning enhances the efficacy of adipose-derived mesenchymal stem cells to accelerate healing of burn wounds[J/OL].Burns Trauma,2021,9:tkab021[2023-12-07].https://pubmed.ncbi.nlm.nih.gov/34514007/.DOI: 10.1093/burnst/tkab021.
[36]	FanB, LiC, SzaladA, et al. Mesenchymal stromal cell-derived exosomes ameliorate peripheral neuropathy in a mouse model of diabetes[J]. Diabetologia, 2020, 63(2): 431-443.DOI: 10.1007/s00125-019-05043-0.
[37]	YangZ,YangY,XuY,et al.Biomimetic nerve guidance conduit containing engineered exosomes of adipose-derived stem cells promotes peripheral nerve regeneration[J].Stem Cell Res Ther,2021,12(1):442.DOI: 10.1186/s13287-021-02528-x.
[38]	YinG, YuB, LiuC, et al. Exosomes produced by adipose-derived stem cells inhibit schwann cells autophagy and promote the regeneration of the myelin sheath [J]. Int J Biochem Cell Biol, 2021, 132:105921. DOI: 10.1016/j.biocel.2021.105921.