Brain injury and neurode­gen­er­a­tion cause irreversible neuron loss. This project models the adult human brain injury environ­ment by decel­lu­lar­iz­ing adult human brain tissue from patients and charac­ter­iz­ing its extra­cel­lu­lar matrix (ECM). Neuronal replace­ment strate­gies will be tested, includ­ing trans­plan­ta­tion of human iPSC-derived neurons and repro­gram­ming of iPSC-derived or adult astro­cytes isolated from resec­tion mater­ial, to define condi­tions that support neuronal replace­ment across diseases and ages.

Neuronal loss occurs due to aging, neurode­gen­er­a­tive diseases, or stroke and is largely irreversible in humans. Regen­er­a­tion in the adult human brain is very limited. Although neuronal trans­plan­ta­tion and direct glia-to-neuron repro­gram­ming repre­sent promis­ing neuronal replace­ment strate­gies, their success is strongly influ­enced by the injury microen­vi­ron­ment. After injury or disease, the extra­cel­lu­lar matrix (ECM) changes signif­i­cantly and can strongly limit neuronal survival and repair. This human injury environ­ment remains poorly under­stood, which limits the devel­op­ment and clini­cal trans­la­tion of regen­er­a­tive strategies.

Models of adult human brain injury microen­vi­ron­ments are estab­lished by decel­lu­lar­iz­ing postmortem brain tissue from differ­ent patholo­gies and age groups and charac­ter­iz­ing ECM compo­si­tion mainly using proteomics. Healthy brain ECM is compared with pathol­ogy-specific ECM to define age- and injury-associ­ated changes relevant for regen­er­a­tion. Two strate­gies for neuronal repair are examined: trans­plan­ta­tion of human iPSC-derived neurons and astro­cyte-to-neuron repro­gram­ming on decel­lu­lar­ized ECM using either young iPSC-derived astro­cytes or adult astro­cytes isolated from resec­tion mater­ial. The influ­ence of the ECM on neuronal survival, stress responses, synap­tic integra­tion, and fate conver­sion is system­at­i­cally analyzed to define how human matrix compo­si­tion affects regen­er­a­tive poten­tial and to optimize neuronal replace­ment strategies.