Therapeutic effects of hipsc-derived glial and neuronal progenitor cells-conditioned medium in experimental ischemic stroke in rats

Transplantation of various types of stem cells as a possible therapy for stroke has been tested for years, and the results are promising. Recent investigations have shown that the administration of the conditioned media obtained after stem cell cultivation can also be effective in the therapy of the central nervous system pathology (hypothesis of their paracrine action). The aim of this study was to evaluate the therapeutic effects of the conditioned medium of hiPSC-derived glial and neuronal progenitor cells in the rat middle cerebral artery occlusion model of the ischemic stroke. Secretory activity of the cultured neuronal and glial progenitor cells was evaluated by proteomic and immunosorbent-based approaches. Therapeutic effects were assessed by overall survival, neurologic deficit and infarct volume dynamics, as well as by the end-point values of the apoptosis-and inflammation-related gene expression levels, the extent of microglia/macrophage infiltration and the numbers of formed blood vessels in the affected area of the brain. As a result, 31% of the protein species discovered in glial progenitor cells-conditioned medium and 45% in neuronal progenitor cells-conditioned medium were cell type specific. The glial progenitor cell-conditioned media showed a higher content of neurotrophins (BDNF, GDNF, CNTF and NGF). We showed that intra-arterial administration of glial progenitor cells-conditioned medium promoted a faster decrease in neurological deficit compared to the control group, reduced microglia/macrophage infiltration, reduced expression of pro-apoptotic gene Bax and pro-inflammatory cytokine gene Tnf, increased expression of anti-inflammatory cytokine genes (Il4, Il10, Il13) and promoted the formation of blood vessels within the damaged area. None of these effects were exerted by the neuronal progenitor cell-conditioned media. The results indicate pronounced cytoprotective, anti-inflammatory and angiogenic properties of soluble factors secreted by glial progenitor cells. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Salikhova D.1, 2 , Bukharova T.1 , Cherkashova E.3, 4 , Namestnikova D.3, 4 , Leonov G.1 , Nikitina M. 2 , Gubskiy I.3, 4 , Akopyan G.4 , Elchaninov A. 2 , Midiber K.2 , Bulatenco N.1 , Mokrousova V.1 , Makarov A. 3 , Yarygin K. 5, 6 , Chekhonin V.3 , Mikhaleva L.2 , Fatkhudinov T. 2, 7 , Goldshtein D. 1, 7
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  • 1 Research Centre for Medical Genetics, Moscow, 115522, Russian Federation
  • 2 Research Institute of Human Morphology, Moscow, 117418, Russian Federation
  • 3 Department of Neurology, Neurosurgery and Medical Genetics, Pirogov Russian National Research Medical University, Moscow, 117997, Russian Federation
  • 4 Radiology and Clinical Physiology Scientific Research Center, Federal State Budgetary Institution “Federal Center of Brain Research and Neurotechnologies of the Federal Medical Biological Agency”, Moscow, 117997, Russian Federation
  • 5 Institute of Biomedical Chemistry, Moscow, 119121, Russian Federation
  • 6 Russian Medical Academy of Continuous Professional Education, Moscow, 125993, Russian Federation
  • 7 Department of Histology, Cytology and Embryology, Peoples’ Friendship University of Russia, Moscow, 117198, Russian Federation
Conditioned medium; Glial progenitor cells; Induced pluripo-tent stem cells (iPSCs); Ischemic stroke; MCAO; Neuronal progenitor cells
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