Stem cell therapy for spinal cord injury improved by plasminogen activator in rats

Researchers from the University of California San Diego (CA, USA) conditioned stem cells with modified tissue-type plasminogen activator (tPA) before delivering the cells into the site of spinal cord injury in rats. 4 months after treatment, the rats possessed an increase in tPA-conditioned neural progenitor cells and improved limb movements. The findings have been published in Scientific Reports.

The researchers generated their neural progenitor cells from induced pluripotent stem cells, before treating the cells with modified tPA in vitro. After 15 minutes, the tPA-conditioned or unconditioned neural progenitor cells were transferred to the spinal cord injury site, in an attempt to discover if tPA had an impact upon injury-related pain.

While the procedure had no effect on pain levels, 2 months on from the initial treatment, the rats possessed 2.5-fold more of the tPA- conditioned neural progenitor cells than unconditioned cells. tPA-conditioned cells were also discovered developing as far as 4 vertebrae away from the site of transplantation.

“It was striking to see at 2 and 4 months the tremendous improvements in the ability of those progenitor cells to survive in the injury cavity,” commented Wendy Campana (University of California San Diego). “Just keeping these cells alive has been very difficult in past studies.”

After 4 months, rats with tPA-conditioned neural progenitor cells had a three-fold increase in motor activity, measured with a scoring system that quantifies a combination of rat joint and limb movements.

“The addition of tPA-treated neural precursors didn’t reduce pain in this model,” explained Campana. “But we also didn’t exacerbate it – and to not see increased pain is important safety information for clinical translation to improve motor outcomes. We also don’t want worsen the pain burden of patients living with spinal cord injuries.”

tPA is already commonly used to treat non-hemorrhagic strokes and break-up blood clots; however, the naturally occurring enzyme also lessens inflammation and improves neuron growth. Considering the clinical implications, the research team utilized an enzymatically inactive form of tPA in their experiments that has the pro-neuronal growth and anti-inflammatory effects but lacked the anticoagulant effect on blood, which could be dangerous to people who have not had a stroke.

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Unfortunately, a limitation of this study is that rats don’t live long enough to encapsulate the long-term changes that may happen in humans; however, it is considered one of the best non-primate models available.

The research team now plan to investigate how modified tPA stimulated the growth of the neural progenitor cells on a molecular level, allowing them to aid spinal cord injury repair.

Source: Shiga Y, Shiga A, Mesci P, et alTissue-type plasminogen activator-primed human iPSC-derived neural progenitor cells promote motor recovery after severe spinal cord injurySci. Rep. 9, 19291 (2019); https://ucsdnews.ucsd.edu/pres… 

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