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“Men ought to know that from the brain, and from the brain only, arise our pleasures, joys, laughter, and jests, as well as our sorrows, pains, griefs and tears”. Already Hippocrates appreciated in the fifth century BC that the brain constitutes the central component orchestrating the processes by which we feel, act, learn and remember [1]. This ample variety of functions our brain performs every second of our lives is based on a tremendous number and diversity of neurons and glial cells.

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We are thrilled by the basic question how specific cellular identities are acquired and maintained.

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Stunningly, all the different kind of neurons and macroglia cells in an adult human brain originate from a small starting population of neural stem cells (NSCs). We use brain organoids to model early human brain development and to elucidate processes orchestrating NSC lineage decisions. Exploiting the fascinating self-organisation capabilities of early neural tissue we study the enigmatic molecular framework dynamically instructing cellular identity changes towards the formation of terminally differentiated neurons and glial cells.

Complementary to these studies interrogating natural differentiation trajectories we employ direct lineage reprogramming to challenge our traditional views on basic aspects of cellular identity, and in particular on processes governing cellular identity acquisition and maintenance. Conceptually, this is particularly fascinating given that during direct lineage reprogramming but not during natural differentiation processes changing cellular identity can occur in the absence of mitosis. We use brain-resident pericytes of the adult human cerebral cortex to study the molecular basis navigating direct lineage conversion from one cellular identity (pericytes) to another one (induced neurons).

 

[1] Kandel, E. R. Principles of neural science. 5th edn, (McGraw-Hill, 2013).