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A New Means to Enhance NSC-based Repair?

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Review of “3K3A–activated protein C stimulates postischemic neuronal repair by human neural stem cells in mice” from Nature Medicine by Stuart P. Atkinson

3K3A-APC is the snappy name given to a mutated form of the blood protease Activated Protein C (APC). This mutant lacks APC’s anti-coagulant activity, so reducing any bleeding risk, but retains APC’s potent cell-signaling activities. Intriguingly, treatment with the 3K3A-APC mutant led to an improvement in symptoms in various disease models leading to a 3K3A-APC trial as a neuroprotectant in ischemic stroke [1, 2]. 

Moving to the realm of stem cells, studies also suggested that 3K3A-APC can stimulate neural stem (NSC) and progenitor (NPC) cell neurogenesis [3]. Therefore, 3K3A-APC may represent a new and exciting therapy for diseases and disorders of the central nervous system (CNS). A new study published in Nature Medicine from the laboratory of Berislav V Zlokovic (University of Southern California, USA) saw this potential and assessed a synergistic role for  3K3A-APC alongside NSC transplantation in the treatment of a mouse model of stroke [4]. 

The study transplanted human fetal NSCs into an experimental infarct lesion in the neocortex of 8-week-old mice followed by 3K3A-APC supplementation via intravenous delivery. Wang et al observed a 3K3A-APC-dependent boost in the survival and proliferation of grafted NSCs that led to a significant improvement in motor and sensorimotor functions at 4-5 weeks after stroke. Furthermore, 3K3A-APC treatment also elevated neuron production from grafted NSCs and promoted the integration of the graft-derived neurons into the host circuitry.

A great result from an awesome combination! This dynamic duo appears to have the ability to mediate substantial repair of post-stroke damage and could, therefore, have great potential for the treatment of a wider number of neurological disorders associated with neuronal loss. How long till we see 3K3A-APC in human trials? Stay tuned to the Stem Cells Portal to keep yourself informed!

References

  1. Lyden P, Levy H, Weymer S, et al. Phase 1 safety, tolerability and pharmacokinetics of 3K3A-APC in healthy adult volunteers. Curr Pharm Des 2013;19:7479-7485.
  2. Safety evaluation of 3K3A-APC in ischemic stroke (RHAPSODY); 2014 August 18; https://clinicaltrials.gov/ct2/show/NCT02222714. 
  3. Wang S, Chandler-Militello D, Lu G, et al. Prospective identification, isolation, and profiling of a telomerase-expressing subpopulation of human neural stem cells, using sox2 enhancer-directed fluorescence-activated cell sorting. J Neurosci 2010;30:14635-14648.
  4. Wang Y, Zhao Z, Rege SV, et al. 3K3A-activated protein C stimulates postischemic neuronal repair by human neural stem cells in mice. Nat Med 2016;22:1050-1055.