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Neural Lineage Differentiation From Pluripotent Stem Cells to Mimic Human Brain Tissues

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Review

Neural Lineage Differentiation From Pluripotent Stem Cells to Mimic Human Brain Tissues

Yean Ju Hong et al. Front Bioeng Biotechnol.

Abstract

Recent advances in induced pluripotent stem cell (iPSC) research have turned limitations of prior and current research into possibilities. iPSCs can differentiate into the desired cell types, are easier to obtain than embryonic stem cells (ESCs), and more importantly, in case they are to be used in research on diseases, they can be obtained directly from the patient. With these advantages, differentiation of iPSCs into various cell types has been conducted in the fields of basic development, cell physiology, and cell therapy research. Differentiation of stem cells into nervous cells has been prevalent among all cell types studied. Starting with the monolayer 2D differentiation method where cells were attached to a dish, substantial efforts have been made to better mimic the in vivo environment and produce cells grown in vitro that closely resemble in vivo state cells. Having surpassed the stage of 3D differentiation, we have now reached the stage of creating tissues called organoids that resemble organs, rather than growing simple cells. In this review, we focus on the central nervous system (CNS) and describe the challenges faced in 2D and 3D differentiation research studies and the processes of overcoming them. We also discuss current studies and future perspectives on brain organoid researches.

Keywords: brain; differentiation; neural; organoid; pluripotent stem cell.

Figures

Figure 1
Figure 1
Morphological differences in diverse neural differentiation approaches. The differentiation of pluripotent stem cells into a neural lineage was developed in a stepwise manner: 2D, 3D, and brain organoid. A depiction of the morphologies of growing neural stem cells and neural rosettes in 2D monolayer cultures. A 3D neurosphere formed with the floating culture technique. Folded brain organoid structure formation after culture embedding in Matrigel and differentiation of pluripotent stem cells. Layer division of early neurons (Tuj-1 positive) and neural progenitors (Sox2 positive) identified by immunocytochemistry. This figure was modified with permission from Stem Cell Biology, published by Life Science Publishing Co.
Figure 2
Figure 2
Timeline of key findings in current brain organoid research. Research on organoids began with two studies. Organotypic, a culture method that divides organs or tissues into smaller units and then re-builds them in vitro, has long been used for the external growth of tissues. This figure illustrates the presence of adult stem cells in different organs, leading to adult stem cell-based organoid study. On a separate note, the basis for the study of brain organoids has been the plethora of studies of self-organizing pluripotent stem cells. Nowadays, research on brain organoids has surpassed the stage of creating region-specific organoids to better mimic the in vivo brain properties, such as vascularization and axis formation.
Figure 3
Figure 3
Possible models for the vascularization of brain organoids. Based on the need for a VEGF signal during the angiogenesis of hBMECs that make up the human BBB, we suggest two potential models using culture devices. One model involves implanting the hBMECs inside the brain organoid and then providing the VEGF signal externally through a permeable cell culture dish to induce angiogenesis as it penetrates the brain organoid. The other model involves creating a gradient by providing the VEGF signal to the opposite side of hBMECs using a 3D cell culture chip device, thereby allowing angiogenesis to occur by penetrating the brain organoid.

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