Page 74 - OR-1-2

host vascular system, establishing functional NVUs. reducing immunogenicity. In addition, gene editing
The V-Organoids survived for several months post- techniques, such as human leukocyte antigen engineering,
transplantation, formed complex cortical structures, and aim to diminish immune recognition and promote graft
expressed mature neuronal markers. Notably, the host acceptance. To further enhance compatibility with host
vasculature infiltrated the transplanted organoids, creating tissue, the use of autologous iPSCs, derived from the
a stable blood supply system that supported long-term patient’s own cells, ensures that the organoids are recognized
survival and reduced necrosis. In addition, the study as “self” by the immune system, thus reducing the risk of
reported the formation of functional synaptic networks rejection. Genetic modifications of the organoids, such
191
and the activation of neuronal circuits, suggesting that as the introduction of immunosuppressive factors such
V-Organoids can integrate into the host brain tissue and as programmed death-ligand 1 or TGF-β, can suppress
potentially replace lost or damaged neuronal populations immune responses and facilitate better integration with the
following brain injury. To further expand the regenerative host tissue. Pre-conditioning the organoids and host tissue
192
83
applications, Shi et al. used the V-Organoids for repairing in a controlled immune environment before implantation
brain injuries. On transplanting V-Organoids into mouse can also help the organoids adapt to the host’s immune
models, they observed that the organoids successfully system. Immunoprotective biomaterials, including
193
integrated with the host’s vascular system, forming new coatings with PEG or self-healing materials, can reduce
blood vessels and promoting tissue regeneration within the immune recognition and provide additional protection.
infarcted cortex. Functional assessments, including motor Finally, clustered regularly interspaced short palindromic
coordination tests, revealed significant improvements in repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)
motor function recovery in mice receiving V-Organoid gene editing can be used to alter the organoid’s genetic
transplants compared to control groups. Histological makeup, lowering its immunogenicity and improving its
analysis confirmed the presence of newly formed cortical survival within the brain. Together, these strategies form a
layers in the infarcted regions, indicating that V-Organoids comprehensive approach to overcoming immune rejection
could not only support structural regeneration but also and enhancing the success of BOs’ transplantation. 194
restore the functionality of the damaged cortex.
Another critical challenge in the long-term integration
The inclusion of vascularization in BOs has significantly of vascularized BOs (V-Organoids) into host tissue is
broadened their regenerative potential. By incorporating ensuring stable vascular anastomosis and functional
functional blood vessels, V-Organoids can better simulate incorporation into the host circulatory and neural
the brain’s in vivo environment, which is crucial for systems. While vascular networks may form within
184
supporting transplanted cells, reducing necrosis, and organoids before transplantation, their structural maturity,
promoting integration with host tissues. This represents a perfusion efficiency, and endothelial compatibility with
promising direction for regenerative medicine, offering a host vasculature remain key determinants of successful
multifaceted approach to repairing neural damage caused engraftment. Inadequate integration can result in
by stroke, traumatic brain injury, and other neurological insufficient blood flow, hypoxia, and necrotic core
conditions. Future research on V-Organoid transplantation formation, particularly in larger organoid constructs where
may focus on enhancing their vascularization and exploring diffusion alone is insufficient to sustain deep tissue regions.
the use of additional factors, such as neural progenitor
cell-derived extracellular vesicles, to further improve their To enhance vascular integration, prevascularization
regenerative capacity. 83,190 with perfusable endothelial networks facilitates early vessel
formation within organoids, enabling more efficient host–
While V-Organoids hold significant promise for organoid vascular connections. Co-transplantation with
195
regenerative medicine, their clinical application faces critical supportive stromal cells, such as pericytes and astrocytes, has
challenges. Immune rejection remains a primary obstacle been shown to stabilize vascular structures and contribute
in tissue transplantation, as the host immune system may to BBB formation. In addition, bioreactor-based dynamic
recognize the organoids as foreign entities, leading to graft culture systems improve endothelial maturation and vascular
rejection. The complexity of the immune system exacerbates complexity before transplantation, increasing the likelihood
this challenge, as various immune cells, including T-cells, of successful integration with the host tissue. The use of
196
macrophages, and dendritic cells, can identify and target the angiogenic biomaterials and bioactive hydrogels provides
transplanted organoids. This immune response significantly a supportive microenvironment that promotes endothelial
limits the long-term survival and functional integration migration, vessel remodeling, and sustained perfusion post-
of the grafts, ultimately hindering the successful clinical implantation. Further advancements in these approaches
application of V-Organoids in regenerative therapies. are essential for optimizing the structural and functional
Several strategies to mitigate immune rejection include incorporation of V-Organoids into host tissue, ultimately
the use of iPSCs to create autologous organoids, thereby enhancing their potential in regenerative medicine.

Volume 1 Issue 2 (2025) 25 doi: 10.36922/or.8162