Mesenchymal stem cell (MSC) homing to kidneys is suppressed by inhibiting interleukin 1-α, tumor necrosis factor-α, or cyclooxygenase-2 signaling
© Burks et al; licensee BioMed Central Ltd. 2015
Published: 30 June 2015
Maximal homing of iv-infused MSC may be critical for cell therapies. Molecular responses from the primarily mechanical effects of pulsed focused ultrasound (pFUS) (i.e., mechanotransduction) in healthy or diseased murine kidneys generate a “molecular zip-code” consisting of local increases in chemoattractants (cytokines, chemokines, cell adhesion molecules) to enhance MSC homing. These findings have substantial potential to improve cell therapies for regenerative medicine. Since molecular signaling post-pFUS drives enhanced MSC homing, other drugs also aiming to treat disease could potentially interfere with molecular responses and subsequent cell migration to targeted tissue thus undermining cell therapy approaches. This study characterized temporal molecular changes post-pFUS to identify critical signals that drive larger changes observed in the chemoattractants and investigates whether inhibition of the early signals could suppress MSC homing to kidneys.
C3H mice received unilateral kidney pFUS (1MHz, 5MPa, 10 ms pulses, 5% duty cycle, VIFU 2000) and kidneys were harvested for ELISA from 10min–72hr after. Pretreatment with drugs included: saline; ibuprofen (nonspecific cyclooxygenase [COX] inhibitor; 30mg/kg, po) 15min pre-pFUS; etanercept (tumor necrosis factor-α inhibitor; 100μg, ip) 72 and 24hr pre-pFUS; or Anakinra (interleukin-1α [IL-1α] inhibitor; 200μg, ip) 48, 24, and 1hr pre-pFUS. Drug-treated kidneys were harvested from 10min–24hr. MSC homing in normal or drug-treated mice included 106 human MSC iv 3hr after kidney pFUS.
Kidneys were harvested 24hr post-injection and MSC were detected by immunofluorescence. Cell counts from pFUS-treated kidneys were compared to untreated contralateral kidneys and ANOVA was used for statistical analysis (p<0.05).
Results and conclusions
This work was funded by the Intramural Research Program at the National Institutes of Health.
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