FNDC5 overexpression promotes the survival rate of bone marrow mesenchymal stem cells after transplantation in a rat cerebral infarction model

Huan Wei; Kangmei Liu; Tingting Wang; Yanping Li; Shaolei Guo; Ling Li

doi:10.21037/atm-21-6868

FNDC5 overexpression promotes the survival rate of bone marrow mesenchymal stem cells after transplantation in a rat cerebral infarction model

Ann Transl Med. 2022 Jan;10(2):90. doi: 10.21037/atm-21-6868.

Authors

Huan Wei^{1

2}, Kangmei Liu¹, Tingting Wang³, Yanping Li², Shaolei Guo⁴, Ling Li¹

Affiliations

¹ Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, National Key Clinical Department and Key Discipline of Neurology, Guangzhou, China.
² Department of Neurology, Yan'an Hospital of Kunming City, The Affiliated Yan'an Hospital of Kunming Medical University, Kunming, China.
³ Department of Geriatrics, Yan'an Hospital of Kunming City, The Affiliated Yan'an Hospital of Kunming Medical University, Kunming, China.
⁴ Department of Neurosurgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.

Abstract

Background: Most bone marrow mesenchymal stem cell (BMSC) death is caused by the harsh ischemia and hypoxic microenvironment, which impacts the therapeutic effects of transplanted BMSCs. Fibronectin type III domain-containing protein 5 (FNDC5) and its cleaved product, irisin, are reportedly involved in cerebral protective effect. Research into whether FNDC5 plays a key role in the survival rate of BMSCs and cerebral infarction (CI) remains inadequate. The present study aimed to clarify the protective role of FNDC5 on the low viability of transplanted BMSCs and improve CI treatment outcomes.

Methods: A lentivirus vector, which drives the expression of FNDC5, was constructed and used to transfect BMSCs. Cell Counting Kit-8 (CCK8), flow cytometry, immunofluorescence, and western blot were performed to evaluate the function of FNDC5-overexpressing BMSCs (BMSCs-OE-FNDC5) exposed to hypoxic and serum deprivation (H/SD) stress. Transmission electron microscopy (TEM) was used to monitor autophagy. In addition, BMSCs were engrafted into a middle cerebral artery occlusion (MCAO) rat model with or without FNDC5-overexpression (OE-FNDC5). The survival rate of transplanted BMSCs was evaluated by 5-ethynyl-2'-deoxyuridine (EdU) labeling. The CI volume was assessed by 2,3,5-triphenyl tetrazolium chloride (TTC) staining.

Results: H/SD stress caused increased cell autophagy, apoptosis, and decreased cell viability of BMSCs, while OE-FNDC5 alleviated these injuries. The in vivo results showed that transplantation of BMSCs-OE-FNDC5 reduced the infarct volume in the rat MCAO model. Furthermore, OE-FNDC5 decreased neuronal apoptosis. The improved therapeutic efficacy of BMSCs-OE-FNDC5 may be attributable to the obviously increased cell survival number after transplantation.

Conclusions: These results indicated that FNDC5 overexpression promotes BMSC survival in a CI model, which might provide a potential therapeutic target.

Keywords: Fibronectin type III domain-containing protein 5 (FNDC5); autophagy; bone marrow mesenchymal stem cells (BMSCs); cell viability; cerebral infarction (CI).