Abstrait

Epileptic seizure suppression by xenograft of engineered human Wharton’s jelly mesenchymal stem cells in kindling model.

Hajar Estiri, Ali Fallah, Bahareh Estiri, Mohammad Estiri, Akbar Farjadfar

Epilepsy is a chronic neurological disorder that needs innovative molecular and cellular approaches to address unmet drug resistance epilepsy in 30% of patients. To push preclinical studies forward, we targeted the human Adenosine Kinase gene (ADK), adenosine removing key enzyme, in Human Wharton's Jelly Mesenchymal Stem Cells (hWJMSCs) by a lentiviral anti-ADK miR-shRNA vector. In this study, we enhanced the therapeutic potential of hWJMSCs as adenosine-releasing stem cells by knockdown of ADK, for suppressing seizures in a kindling model of epilepsy among male Wistar rats. After the lentiviral transduction of hWJMSCs with anti-ADK miR-shRNA expression cassette, we implicated the down regulation of ADK up to 95% in RNA and protein level by qRT-PCR and western blot, respectively. Adenosine concentration reached 10 ng per ml of the culture medium when incubating 105 engineered hWJMSCs for 8 hours. Cell transplantation in pentylenetetrazole-induced kindled rats significantly decreased the amplitude, duration, and seizure spike frequency while increased the latency of appearance of the first seizure spike on days 7 and 14 of EEG recording. Behavioral seizure monitoring showed complete protection from convulsive seizures in 100% (n=20) and 83% (n=18) of kindled rats for the first and second weeks after cell graft respectively. An animal showed complete seizure protection (n=16) after 8 weeks. Our findings suggest that adenosine releasing hWJMSC might be a striking source in cell-based gene therapy and may have a therapeutic perspective in epilepsy.