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The generation of astrocytes derived from human induced pluripotent stem cells (hiPSC): a powerful tool for the neuroinflammation study

Grant number: 19/08177-3
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): June 01, 2019
Effective date (End): November 30, 2020
Field of knowledge:Biological Sciences - Biochemistry - Molecular Biology
Principal Investigator:Fernando de Queiroz Cunha
Grantee:Naira Lopes Bibó
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:13/08216-2 - CRID - Center for Research in Inflammatory Diseases, AP.CEPID

Abstract

Glia cells (microglia, astrocytes and satellite cells) are involved in the control of neurogenesis, neuronal survival, transmission, and immune surveillance. Various studies have demonstrated the importance of these cells in the development and maintenance of disorders in the central and peripheral nervous systems, such as neurodegenerative diseases and pain. Astrocytes are the most prevalent glial cells in the central nervous system and act in the synapses formation neurotransmitters uptake and recycling7 and maintenance of the blood-brain barrier by controlling fluid, pH and metabolic changes in the central nervous system. Defective astrocytes are involved in various neurological disorders such as Alzheimer's, Parkinson's, dementia and sclerosis. In the context of neuropathic pain, glial cells can be over stimulated by the proinflammatory cytokines released from the injured nerve, with astrocytes being crucial for the neuroinflammatory response modulation. Studies have been described that neuroinflammation and ischemia induced two different types of reactive astrocytes, termed ''A1'' and ''A2,'' respectively, being A1 astrocytes proinflammatory and neurotoxic while the A2 subpopulation presented an anti-inflammatory and neuroprotective profile. Thus, it is important to note that in the neuropathy context, the presence of A1 astrocytes is favoured, leading to an increase in neuroinflammation, that may culminating in the neuropathic pain maintenance. However, the molecular mechanisms that govern the phenotype switch of astrocytes remain unclear. In this context, the aim of the present work is to differentiate and characterize astrocytes derived from human induced pluripotent stem cells (hiPSC) to be subsequently used as powerful tool to study the signalling pathways involved in the induction of reactive astrocytes A1, aiming at discovering new pharmacological targets for treatment of the neuropathic pain. The generation of astrocytes derived from primary human cells represents an invaluable tool for translational research, since unlike immortalized cell lines, the primary cells preserve the genetic background from the parental cells. In addition, the use of primary human cells could prevent the limitations of mouse-derived cells, such as limited yield, the intrinsic variability and the non-human nature of the cells.