iPSC-MSCs with High Intrinsic MIRO1 and Sensitivity to TNF-α Yield Efficacious Mitochondrial Transfer to Rescue Anthracycline-Induced Cardiomyopathy.

Mesenchymal stem cells (MSCs) can donate mitochondria and rescue anthracycline-induced cardiomyocyte (CM) damage, although the underlying mechanisms remain elusive. We determined that the superior efficiency of mitochondrial transfer by human induced-pluripotent-stem-cell-derived MSCs (iPSC-MSCs) compared with bone marrow-derived MSCs (BM-MSCs) is due to high expression of intrinsic Rho GTPase 1 (MIRO1). Further, due to a higher level of TNFαIP2 expression, iPSC-MSCs are more responsive to tumor necrosis factor alpha (TNF-α)-induced tunneling nanotube (TNT) formation for mitochondrial transfer to CMs, which is regulated via the TNF-α/NF-κB/TNFαIP2 signaling pathway. Inhibition of TNFαIP2 or MIRO1 in iPSC-MSCs reduced the efficiency of mitochondrial transfer and decreased CMs protection. Compared with BM-MSCs, transplantation of iPSC-MSCs into a mouse model of anthracycline-induced cardiomyopathy resulted in more human mitochondrial retention and bioenergetic preservation in heart tissue. Efficacious transfer of mitochondria from iPSC-MSCs to CMs, due to higher MIRO1 expression and responsiveness to TNF-α-induced nanotube formation, effectively attenuates anthracycline-induced CM damage.

Insensitivity of Human iPS Cells-Derived Mesenchymal Stem Cells to Interferon-γ-induced HLA Expression Potentiates Repair Efficiency of Hind Limb Ischemia in Immune Humanized NOD Scid Gamma Mice.

Adult mesenchymal stem cells (MSCs) are immunoprivileged cells due to the low expression of major histocompatibility complex (MHC) II molecules. However, the expression of MHC molecules in human-induced pluripotent stem cells (iPSCs)-derived MSCs has not been investigated. Here, we examined the expression of human leukocyte antigen (HLA) in human MSCs derived from iPSCs, fetuses, and adult bone marrow (BM) after stimulation with interferon-γ (IFN-γ), compared their repair efficacy, cell retention, inflammation, and HLA II expression in immune humanized NOD Scid gamma (NSG) mice of hind limb ischemia. In the absence of IFN-γ stimulation, HLA-II was expressed only in BM-MSCs after 7 days. Two and seven days after stimulation, high levels of HLA-II were observed in BM-MSCs, intermediate levels were found in fetal-MSCs, and very low levels in iPSC-MSCs. The levels of p-STAT1, interferon regulatory factor 1, and class II transactivator exhibited similar phenomena. Moreover, p-STAT1 antagonist significantly reversed the high expression of HLA-II in BM-MSCs. Compared to adult BM-MSCs, transplanting iPSC-MSCs into hu-PBMNC NSG mice revealed markedly more survival iPSC-MSCs, less inflammatory cell accumulations, and better recovery of hind limb ischemia. The expression of HLA-II in MSCs in the ischemia limbs was detected in BM-MSCs group but not in iPSC-MSCs group at 7 and 21 days after transplantation. Our results demonstrate that, compared to adult MSCs, human iPSC-MSCs are insensitive to proinflammatory IFN-γ-induced HLA-II expression and iPSC-MSCs have a stronger immune privilege after transplantation. It may attribute to a better therapeutic efficacy in allogeneic transplantation.

Effects and mechanism of turmeric vasorelaxation of the thoracic aorta in hypercholesterolemic rats.

An extract of Curcuma longa was tested in hypercholesterolemic rats to investigate its potential therapeutic effect on vascular conditions. Four experimental groups were used: normal diet (ND) control group, high cholesterol diet (HCD) group, and HCD subgroups supplemented with turmeric extract at 100 or 300 mg/kg of body weight (HCD100Tur and HCD300Tur groups, respectively). Turmeric extract was fed orally to animals, and dietary treatments lasted for 28 days. Hypercholesterolemia developed in the HCD, HCD100Tur, and HCD300Tur rats. Segments of the thoracic aorta were isolated, and an organ bath experiment was used to assess the vasorelaxation capability among all rats. Rats fed only HCD showed a marked decrease in acetylcholine-induced vasorelaxation compared with ND control rats. The HCD100Tur and HCD300Tur rats showed significant improvement in vasorelaxation compared with HCD rats. When vasorelaxation was induced by high concentrations of sodium nitroprusside, no differences in vasorelaxation were observed among the four groups of rats. A mechanistic study showed that HCD100Tur and HCD300Tur rats had significantly higher levels of the antioxidant enzymes superoxide dismutase and glutathione peroxidase than HCD rats. The transcript levels of heat shock protein 70 (hsp70), bcl2, bax-α, caspase (casp3), and glyceraldehyde 3-phosphate dehydrogenase in aortic tissues indicated that hypercholesterolemia significantly increased the expression of bax-α and casp3 but down-regulated bcl2 expression compared with the control group. Turmeric increased the expression of hsp70 and bcl2 but greatly reduced casp3 expression, indicating that turmeric improves vasorelaxation of the aorta in hypercholesterolemic rats by increasing antioxidant enzyme activities and likely suppressing apoptosis.

Attenuation of fatty liver and prevention of hypercholesterolemia by extract of Curcuma longa through regulating the expression of CYP7A1, LDL-receptor, HO-1, and HMG-CoA reductase.

UNLABELLED: The extract of Curcuma longa, better known as turmeric, was orally administered to experimental rats that were fed a high-cholesterol diet to investigate whether it could regulate plasma lipids and cholesterol levels and possibly improve hepatic conditions. With turmeric supplements, rats showed a significant decrease in total plasma cholesterol and low-density lipoprotein cholesterol but an increase in high-density lipoprotein cholesterol when compared with rats that were fed a high-cholesterol diet alone. Fatty liver developed in hypercholesterolemic rats with the high-cholesterol diet treatment, and this condition was markedly improved when rats were provided with turmeric supplements at 100 mg/kg or 300 mg/kg of body mass. The turmeric treatment resulted in a significant decrease in the total amount of hepatic lipid. Histological staining of liver tissues with Sudan III and hematoxylin showed that rats fed with a high-cholesterol diet alone had more and larger granular fat bodies than rats having turmeric extract supplementation in their high-cholesterol diet. Reverse-transcription polymerase chain reaction was used to assess the expression levels of enzymes involved in fat metabolism and cellular homeostasis in experimental rat livers. The results showed that rats fed a high-cholesterol diet supplemented with turmeric extract had a significant increase in the expression of cholesterol 7 α-hydroxylase, hemeoxygenase 1, and low-density lipoprotein receptors but a significant decrease in 3-hydroxy-3-methyl-glutaryl-CoA reductase level when compared with rats fed a normal or high-cholesterol diet, showing that turmeric prevents hypercholesterolemia and the formation of fatty liver by the modulation of expressions of enzymes that are important to cholesterol metabolism. PRACTICAL APPLICATION: Turmeric may be considered a functional food for regulating plasma cholesterol levels and preventing the development of fatty liver in people who frequently consume a high-cholesterol diet.