KLF7 overexpression in bone marrow stromal stem cells graft transplantation promotes sciatic nerve regeneration

Abstract

Objective. Our previous study demonstrated that the transcription factor, Krüppel-like Factor 7 (KLF7), stimulates axon regeneration following peripheral nerve injury. In the present study, we used a gene therapy approach to overexpress KLF7 in bone marrow-derived stem/stromal cells (BMSCs) as support cells, combined with acellular nerve allografts (ANAs) and determined the potential therapeutic efficacy of a KLF7-transfected BMSC nerve graft transplantation in a rodent model for sciatic nerve injury and repair. Approach. We efficiently transfected BMSCs with adeno-associated virus (AAV)-KLF7, which were then seeded in ANAs for bridging sciatic nerve defects. Main results. KLF7 overexpression promotes proliferation, survival, and Schwann-like cell differentiation of BMSCs in vitro. In vivo, KLF7 overexpression promotes transplanted BMSCs survival and myelinated fiber regeneration in regenerating ANAs; however, KLF7 did not improve Schwann-like cell differentiation of BMSCs within in the nerve grafts. KLF7-BMSCs significantly upregulated expression and secretion of neurotrophic factors by BMSCs, including nerve growth factor, ciliary neurotrophic factor, brain-derived neurotrophic factor, and glial cell line-derived neurotrophic factor in regenerating ANA. KLF7-BMSCs also improved motor axon regeneration, and subsequent neuromuscular innervation and prevention of muscle atrophy. These benefits were associated with increased motor functional recovery of regenerating ANAs. Significance. Our findings suggest that KLF7-BMSCs promoted peripheral nerve axon regeneration and myelination, and ultimately, motor functional recovery. The mechanism of KLF7 action may be related to its ability to enhance transplanted BMSCs survival and secrete neurotrophic factors rather than Schwann-like cell differentiation. This study provides novel foundational data connecting the benefits of KLF7 in neural injury and repair to BMSC biology and function, and demonstrates a potential combination approach for the treatment of injured peripheral nerve via nerve graft transplant.

Circular RNA circUBE2J2 acts as the sponge of microRNA-370-5P to suppress hepatocellular carcinoma progression

“…KLF7 is a member of the Kruppel-like transcriptional regulator family. Members of the KLF family have established roles in tumor cell proliferation, differentiation, survival, cell fate, stress response, and the tumor-initiating properties of cancer stem-like cells [ 33 ]. Knockdown of KLF7 inhibits the expression of IFN-stimulated genes, which are necessary for KLF7-mediated PDAC tumor growth and metastasis [ 34 ].…”

Combinatory transplantation of mesenchymal stem cells with flavonoid small molecule in acellular nerve graft promotes sciatic nerve regeneration

“…In preparation of BMSCs for use in the study, BMSCs were obtained from adult female mice and cultured in standard culture medium consisting of Dulbecco’s modified Eagle’s medium (DMEM) with 10% fetal bovine serum (FBS, ThermoFisher Scientific, Pittsburgh, PA, USA) as described previously. 3 In brief, bone marrow was removed from the marrow cavity of dissected mouse long bones and the isolated cells were centrifuged in culture medium. The supernatant was removed and cells in the pellet were re-suspended in standard culture medium and cultured in a humidified 37°C incubator containing 5% CO 2 for 48 h. Cells that did not adhere to the culture dish were removed.…”

“…In demonstration of other positive aspects of BMSCs in such therapy is the differentiation capacity toward Schwann cell lineage and the production and secretion of various neurotrophic factors. 3,4 Of the neurotrophic factors, brain derived neurotrophic factor (BDNF) is one the most studied and therapeutically beneficial for axon regeneration in peripheral nerves. In the nerve, BDNF is produced and secreted by transformed Schwann cells, and imparts axon elongation through binding and activation of the tropomycin receptor kinase B (TrkB) on regenerating axons.…”

“…In demonstration of other positive aspects of BMSCs in such therapy is the differentiation capacity toward Schwann cell lineage and the production and secretion of various neurotrophic factors. 3 , 4 …”

Krüppel-like factor 7 attenuates hippocampal neuronal injury after traumatic brain injury

“…KLF6 and KLF7 act through the same transcriptional targets and DNA-binding domains (Veldman et al, 2007). Thus, KLF7 may also be associated with JAK2/STAT3 signaling because accumulating evidence indicates that KLF7 promotes neuronal survival and axonal regeneration after nerve injury (Li et al, 2017a(Li et al, , 2019bWang et al, 2017). The mechanisms of KLF7-mediated TBI pathogenesis, as well as the effects of its intervention, are worthy of investigation.…”