Hypoxia preconditioning promotes bone marrow mesenchymal stem cells survival by inducing HIF-1α in injured neuronal cells derived exosomes culture system

Abstract

Bone marrow derived stem cells (BMSCs) transplantation are viewed as a promising therapeutic candidate for spinal cord injury (SCI). However, the inflammatory microenvironment in the spinal cord following SCI limits the survival and efficacy of transplanted BMSCs. In this study, we investigate whether injured neuronal cells derived exosomes would influence the survival of transplanted BMSCs after SCI. In order to mimic the microenvironment in SCI that the neuronal cells or transplanted BMSCs suffer in vivo, PC12 cells conditioned medium and PC12 cell’s exosomes collected from H2O2-treated PC12 cell’s culture medium were cultured with BMSCs under oxidative stress in vitro. PC12 cells conditioned medium and PC12 cell’s exosomes significantly accelerated the apoptosis of BMSCs induced by H2O2. Moreover, the cleaved caspase-3, cytochrome (Cyt) C, lactate dehydrogenase (LDH) releases, and apoptotic percentage were increased, and the ratio of Bcl-2/Bax and cell viability were decreased. Inhibition of exosome secretion via Rab27a small interfering RNA prevented BMSCs apoptosis in vitro. In addition, hypoxia-preconditioned promoted the survival of BMSCs under oxidative stress both in vivo after SCI and in vitro. Our results also indicate that HIF-1α plays a central role in the survival of BMSCs in hypoxia pretreatment under oxidative stress conditions. siRNA-HIF-1α increased apoptosis of BMSCs; in contrast, HIF-1α inducer FG-4592 attenuated apoptosis of BMSCs. Taken together, we found that the injured PC12 cells derived exosomes accelerate BMSCs apoptosis after SCI and in vitro, hypoxia pretreatment or activating expression of HIF-1α to be important in the survival of BMSCs after transplantation, which provides a foundation for application of BMSCs in therapeutic potential for SCI.

MicroRNA Profiling of Exosomes Derived from Red Blood Cell Units: Implications in Transfusion-Related Immunomodulation

“…However, none of the 3 miRNAs could serve as a biomarker for predicting storage lesions and monitoring the quality of RBC units. Although mature RBCs can not generate new RNA molecules and exosomal RNA molecules are possibly degraded with the extending storage time, we can find increasing of these 3 miRNAs during storage and attribute this phenomenon to the changes in microenvironment of stored RBCs which were previously reported [32], leading to the changes in contents of exosomes [13,27,29,30]. However, high abundance of exosomal miR-451a may mark it as an important regulatory miRNA in the recipients.…”

“…However, the role and mechanisms of exosomes (RBCs-derived) in transfusion-related immunomodulation await clear elucidation. Secretion and contents of exosomes are regulated by different microenvironments [13,27,29,30]. The contents of exosomes (RBC-derived), stored in ACD-A solution, are still unknown.…”

Preconditioned and Genetically Modified Stem Cells for Myocardial Infarction Treatment

“…Hypoxic preconditioning (HPC) could advance the efficiency of stem cell therapy. Indeed, in multiple studies, the exposure of stem cells to hypoxic conditions prior to transplantation resulted in improved survival, enhanced proliferation and differentiation, and reduced senescence [ 41 , 42 , 43 , 44 ]. The alternation of hypoxic and normal oxygen conditions promotes multipotency and the expression of pro-survival genes and trophic factors in MSCs [ 31 , 45 ].…”

New insights into the immunomodulatory role of exosomes in cardiovascular disease

“…Shao et al (2017) found that mesenchymal stem cell-derived exosomes (MSC-Exos) alleviated the inflammatory response and improved cardiac function by decreasing the infiltration of inflammatory cells in the infarct area via down-regulating the expression of CD68. In order to enhance their cardiaoprotective effect, exosomes can be pretreated by hypoxia preconditioning (Luo et al, 2019), gene programming (Wang et al, 2018), or drug intervention (Huang et al, 2019). Pan et al (2019a) showed that exosomes derived from miR-146a-modified adipose-derived stem cells ADSC-Exos inhibit the release of interleukin-6 (IL-6), interleukin-1β (IL-1β ) and tumor necrosis factor-α (TNF-α), as well as reducing the local inflammatory response, improving the local microenvironment, and attenuating acute myocardial infarction-induced myocardial damage via the down-regulation of early growth response factor 1 (EGR1).…”