Dose-dependent benefits of iron-magnetic nanoparticle-coated human umbilical-derived mesenchymal stem cell treatment in rat intracranial hemorrhage model

Abstract

Background This study tested whether two doses of human umbilical-derived mesenchymal stem cells (hUC-MSCs) were superior to one dose for protecting the brain against intracranial hemorrhage (ICH) induced by intracranial injection collagenase and the capacity of ironic-magnetic-nanoparticles (Ir-MNa) coated hUC-MSCs tracked by MRI. Methods and results Adult male SD rats (n = 40) were equally categorized into group 1 (sham-operated-control), group 2 (ICH), group 3 [ICH + Ir-MNa-coated hUC-MSCs/1.2 × 106 cells with an extracorporeal magnet over rat head (eCMag)/administered by left internal carotid artery (LICA) at post-3 h ICH], and group 4 (ICH + Ir-MNa-coated hUC-MSCs/1.2 × 106 cells with an eCMag/administered post-3 h ICH by LICA and 24 h by IV) and euthanized by day 28. The result showed that by day 28 after ICH induction the neurological function was severely impaired in group 2 than in group 1 that was significantly improved in group 3 and further significantly improved in group 4, whereas ICH volume exhibited an opposite pattern of neurological impairment among the groups (all p < 0.0001). Brain MRI demonstrated that by 4 h after ICH, Ir-MNa-coated hUC-MSCs were abundantly identified in ischemic area in group 4. The protein expressions of inflammatory (TNF-α/MMP-9/IL-1ß/iNOS)/oxidative-stress (NOX-1/NOX-2/oxidized protein)/apoptotic (caspase-3/mitochondrial Bax/PARP)/fibrotic (Smad3/TGF-ß)/mitochondrial-damaged (cytosolic-cytochrome-C) biomarkers displayed an identical pattern of neurological impairment among the groups (all p < 0.0001). The cellular expressions of inflammation (CD68+/CD11b+)/brain edema (AQP4+) biomarkers exhibited an identical pattern, whereas the neuronal-myelin (Doublecortin+/NeuN/nestin) biomarkers displayed an opposite pattern of neurological impairment (all p < 0.0001). Conclusion Two doses of hUC-MSCs were superior to just one dose for protecting the brain against ICH-induced damage and Ir-MNa-coated hUC-MSCs offered a well adopted method for tracking hUC-MSCs homing into the brain.

Repeated administration of adipose-derived mesenchymal stem cells added on beneficial effects of empagliflozin on protecting renal function in diabetic kidney disease rat

“…An essential finding in the present study was that not only AMDSCs but also EMPA therapy effectively protected the residual renal function in DKD animals, i.e., preventing the upregulations of circulatory levels of BUN and creatinine and the ratio of urine protein to urine creatinine. In this way, our findings were consistent with the findings of previous studies [ 26 , 27 , 29 , 31 , 32 ]. Surprisingly, while the positive impact of ADMSCs and EMPA therapy on protecting kidney function in CKD or DKD settings is still lacking adequate evidence to address whether combined ADMSC and EMPA therapy would offer a synergic effect for further improving renal function in DKD settings.…”

“…A principal finding in the present study was that all of the molecular-cellular perturbations, including oxidative stress, inflammatory, fibrotic, DNA-damaged and autophagic biomarkers, were notably increased in DKD animals as compared with SC animals that were significantly suppressed by ADMSCs or EMPA treatment and further significantly suppressed by these therapeutic components. In this way, our findings, in addition to strengthening the findings of the previous studies [ 26 , 27 , 29 , 31 , 32 ], could partially vindicate why the urine protein and kidney injury score were markedly alleviated by ADMSCs-EMPA therapy.…”

“…Plentiful evidence from clinical trials [ [13] , [14] , [15] ] and animal model studies [ 17 ]has demonstrated that SGLT2 inhibitors effectively protected the residual renal function in the DKD setting. Additionally, numerous data [ 26 , 27 , 29 , 31 , 32 ] have proved that cell therapy, especially those of MSCs, effectively protects the renal function in CKD setting. An essential finding in the present study was that not only AMDSCs but also EMPA therapy effectively protected the residual renal function in DKD animals, i.e., preventing the upregulations of circulatory levels of BUN and creatinine and the ratio of urine protein to urine creatinine.…”

“…Link between CKD and eliciting of oxidative stress, inflammation and fibrosis has been well understood in CKD/DKD settings [ 26 , 27 , 29 , 31 , 32 ]. A principal finding in the present study was that all of the molecular-cellular perturbations, including oxidative stress, inflammatory, fibrotic, DNA-damaged and autophagic biomarkers, were notably increased in DKD animals as compared with SC animals that were significantly suppressed by ADMSCs or EMPA treatment and further significantly suppressed by these therapeutic components.…”

“…Additionally, copious animal model studies and a few clinical trials have shown that cell-based therapy furnished significant advantages for settings of CKD, acute kidney injury, or CRS [ [26] , [27] , [28] , [29] , [30] ]. Furthermore, our recent studies have proved that cell-based therapy endured a dose-dependent effect (i.e., a single dose was inferior to two doses) on improving the outcomes in damaged organs [ 31 , 32 ]. Based on these subjects [ [12] , [13] , [14] , [15] , [16] , [17] , [18] , [19] , [20] , [21] , [22] , [23] , [24] , [26] , [27] , [28] , [29] , [30] , [31] , [32] , [33] , [34] ], it is reasonable to believe that repeated doses of ADMSCs administration might facilitate the therapeutic potential of EMPA on DKD rodents.…”