Addition of adipose tissue-derived mesenchymal stem cells improves empagliflozin therapy for alleviating hyperglycemia--induced neuropathy

Hung-Sheng Lin; Chien-Hui Yang; Tsung-Cheng Yin; Pei-Hsun Sung; John Y Chiang; Pei-Lin Shao; Yi-Ling Chen; Chi-Ruei Huang; Hon-Kan Yip; Kuan-Hung Chen

Addition of adipose tissue-derived mesenchymal stem cells improves empagliflozin therapy for alleviating hyperglycemia--induced neuropathy

Am J Transl Res. 2023 Oct 15;15(10):6264-6285. eCollection 2023.

Authors

Hung-Sheng Lin¹, Chien-Hui Yang², Tsung-Cheng Yin³, Pei-Hsun Sung⁴, John Y Chiang⁵, Pei-Lin Shao⁶, Yi-Ling Chen⁴, Chi-Ruei Huang⁴, Hon-Kan Yip^{4

6

7

8

9

10}, Kuan-Hung Chen²

Affiliations

¹ Division of Neurology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung 83301, Taiwan.
² Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung 83301, Taiwan.
³ Department of Orthopaedic Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung 83301, Taiwan.
⁴ Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung 83301, Taiwan.
⁵ Department of Computer Science and Engineering, National Sun Yat-Sen University Kaohsiung 80424, Taiwan.
⁶ Department of Nursing, Asia University Taichung 41354, Taiwan.
⁷ Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital Kaohsiung 83301, Taiwan.
⁸ School of Medicine, College of Medicine, Chang Gung University Taoyuan 333, Taiwan.
⁹ Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital Kaohsiung 83301, Taiwan.
¹⁰ Department of Medical Research, China Medical University Hospital, China Medical University Taichung 40402, Taiwan.

PMID: 37969202
PMCID: PMC10641353

Abstract

Background: We examined the impact of adipose-derived mesenchymal stem cell (ADMSC)-facilitated empagliflozin (EMPA) therapy for alleviating hyperglycemic induced neuropathy [i.e., diabetic neuropathy (DN)].

Methods: Study constituted N2a cell culture and rats to be classified into groups 1 (sham-operated-control)/2 (DN)/3 (DN + empagliflozin/20 mg/kg/daily orally for 6 weeks since post-day-7 DN induction)/4 (DN + ADMSCs/1.2 × 10⁶ cells by vein transfusion at time intervals of 1/3/5 weeks after DN induction)/5 (DN + empagliflozin + ADMSCs) and sacrificed by day-42 after DN induction.

Results: In vitro results showed that, compared to N2a cells, the cellular levels of senescence/DNA-damage and protein expressions of oxidative-stress (OS), apoptotic, autophagic and inflammatory biomarkers were significantly higher in N2a + glucose (25 mM) but were significantly reversed in N2a + glucose + ADMSCs, whereas the cellular levels of mitochondrial cytochrome C and protein levels of anti-oxidants displayed an opposite pattern of OS (all P<0.001). The above-mentioned parameters (i.e., OS/apoptosis/fibrosis/autophagy/DNA-damage) were lowest in N2a cells, highest in N2a + glucose and significantly higher in N2a + glucose + EMPA (50 μM) than in N2a + glucose + EMPA (150 μM) (all P<0.001). By days 7/14/21/28/35/42 after DN induction, the values of thermal paw-withdrawal-latency (TPWL)/mechanical-paw-withdrawal-threshold were highest in group 1 and significantly progressively increased from groups 2/4/3/5 (all P<0.0001). The cellular levels of unmyelinated C- and myelinated A-δ fibers, and protein levels of OS/apoptotic/DNA-damaged/fibrotic/autophagic/inflammatory/pain-facilitated/voltage-gated sodium channel biomarkers in L4-L5 levels of dorsal-root-ganglia exhibited an contradictory manner of TPWL among the groups (all P<0.0001).

Conclusions: Combination of EMPA and ADMSC therapy was superior to either alone for improving outcomes of DN.

Keywords: Diabetic neuropathy; empagliflozin; inflammation; mesenchymal stem cells; oxidative stress.