Functional recovery through the plastic adaptation of organoid grafts in cortical tissue

Abstract

The lack of effective therapeutic options for patients suffering from neurological impairments related to acquired brain damage requires novel translational strategies, among which transplantation of neural tissue is receiving strong attention. One of the most recent developments involves the implantation of brain organoid models, derived from embryonic or induced pluripotent stem cells, into damaged rodent cortices. While this approach is gaining popularity, the extent of graft integration within the host tissue remains poorly understood. This review aims to examine whether xenotransplanting organoids into cortical tissue induces functional recovery and plastic adaptation to the damaged implantation sites. Physiological indications of grafted organoid plasticity and integration into the host included viability, corticogenesis, vascularisation, growth, and the development of area-specific morphological identities. The functional integration into host neural circuitry has been probed by tracing of axonal projection growth according to implantation sites, but also through observations of spontaneous, stimulus evoked, and selectively tuned activity of grafted neurons. Finally, some studies also investigated whether the engraftment procedure facilitated behavioural recovery in tasks requiring motor, memory, or reward-seeking functions. Overall, organoid grafts show signs of progressive anatomical, functional, and behaviourally-relevant integration within the damaged host cortices. Yet, further investigation is necessary before this transplantation approach can be actually translated into a robust method to achieve functional restoration in patients suffering from brain damage.

Keywords: Brain damage; Brain organoids; Functional recovery; Organoid transplantation; Xenotransplantation.

Fig. 1

Depiction of transplantation model methodologies and approaches to assessing graft integration. Sample tissue selected for engraftment is commonly derived from pluripotent stem cells (PSCs), such as iPSCs or ESCs, through culturing. This enables the generation of cellular grafts like proliferative cells (NPCs, NSCs, NESCs) or various types of neurons and differentiated cortical cells. On the other hand, iPSCs and ESCs may also be cultured into organoids and more advanced assembloids. Furthermore, organoids and assembloids can be dissociated into cells. This is usually conducted to investigate graft integration outcomes of structured organoids/assembloids in comparison to its disassembled and unorganised cellular contents. The cellular or organoid tissue is then selected for engraftment via injection or manual placement into a specific region of the host cortex, depending on the employed transplantation model. The hosts, typically rodents, are usually subject to cortical damage prior to the transplantation. The models of neural damage previously utilized are induced strokes (middle cerebral artery occlusion (MCAO), focal injury stroke), lesioning by aspiration or direct tissue removal, and procedures mimicking TBI. Specifically for organoids, these damage models are used to create cortical cavities to fit the size of grafts for implantation. In general, transplanting grafts into lesioned cortices is conducted for the investigation of cortical regeneration following the engraftment. This regeneration is probed by several validation paradigms, including examining the extents of anatomical integration (survival, growth, vascularisation, structural integrity and cellular composition of the grafts), functional recovery (functional reconstruction via synaptic integration and electrophysiological activity of grafted neurons), or behavioural outcomes of the grafting procedure. Created in BioRender. Ondriš, J. (2025) https://BioRender.com/s34g864