Vascularized organoids

Organoids are self-organizing structures derived from different cell types such as induced pluripotent stem cells or multipotent adult tissue stem cells. The organoids’ self-organization process is manifested in 3D culture systems that allow biologically relevant cell-cell and cell-matrix interactions. These 3D multicellular tissue constructs are able to mimic in vitro their corresponding in vivo organ. 1 2 3

Balanced organogenesis requires orchestrating multiple cellular interactions to create the collective cell behavior that progressively shapes developing tissues. Consequently, this technology can be used to model human organ development and various human pathologies ‘in a dish’’. Also, patient-derived organoids hold promise to predict drug response in a personalized manner. 4 5

One of the critical limitations in using organoid-based approaches to generate functional tissue is related to the fact that organoids cease to increase and develop a necrotic core upon reaching a specific size. The long-term survival of organoid grafts in a host requires vascularization to satisfy the adequate delivery of oxygen, nutrients, and waste exchange. 2 6

Figure 1: An overview of vascularization techniques. 2

Brain vascularized organoids offer an unprecedented opportunity to model human brain development and disease. 7 Pham et al. (2018) developed an approach to vascularize brain organoids with patients’ endothelial cells (ECs) by growing induced pluripotent stem cells (iPSCs) into patient’s whole-brain organoids. Simultaneously, iPSCs from the same patient were differentiated into ECs. Coating brain organoids on day 34 with ECs led to robust vascularization of the organoid after 3–5 weeks in vitro and two weeks in vivo. 8

Figure 2: Penetration of capillaries into the outer layers of the organoid in vitro.8


Likewise, kidney organoids can be generated from human pluripotent stem cells (PSCs) using protocols that resemble the kidney’s embryonic development. 9 In 2019, an in vitro method for culturing kidney organoids on millifluidic chips was reported. This method significantly expanded their endogenous pool of endothelial progenitor cells (EPCs) and generated vascular networks with perfusable lumens surrounded by mural cells. Also, it exhibited more mature podocyte and tubular compartments with enhanced cellular polarity and adult gene expression than static controls. The ability to induce substantial vascularization and morphological maturation of kidney organoids in vitro opens a new path for studying kidney development, disease, and regeneration. 10


REFERENCES


1. de Melo, B. A. G., Benincasa, J. C., Cruz, E. M., Maricato, J. T. & Porcionatto, M. A. 3D culture models to study SARS-CoV-2 infectivity and antiviral candidates: From spheroids to bioprinting. Biomed. J. 44, 31–42 (2021).

2. Grebenyuk, S. & Ranga, A. Engineering Organoid Vascularization. Frontiers in Bioengineering and Biotechnology vol. 7 (2019).

3. Hynds, R. E. & Giangreco, A. Concise review: the relevance of human stem cell-derived organoid models for epithelial translational medicine. Stem Cells 31, 417–422 (2013).

4. Clevers, H. Modeling Development and Disease with Organoids. Cell 165, 1586–1597 (2016).

5. Eiraku, M. et al. Self-organizing optic-cup morphogenesis in three-dimensional culture. Nature 472, 51–56 (2011).

6. Shi, Y. et al. Vascularized human cortical organoids (vOrganoids) model cortical development in vivo. PLoS Biol. 18, e3000705 (2020).

7. Mansour, A. A. et al. An in vivo model of functional and vascularized human brain organoids. Nature Biotechnology vol. 36 432–441 (2018).

8. Pham, M. T. et al. Generation of human vascularized brain organoids. Neuroreport 29, 588–593 (2018).

9. Koning, M., van den Berg, C. W. & Rabelink, T. J. Stem cell-derived kidney organoids: engineering the vasculature. Cell. Mol. Life Sci. 77, 2257–2273 (2020).

10. Homan, K. A. et al. Flow-enhanced vascularization and maturation of kidney organoids in vitro. Nat. Methods 16, 255–262 (2019).


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