Cerebral organoids model human brain development and microcephaly

Abstract

The complexity of the human brain has made it difficult to study many brain disorders in model organisms, and highlights the need for an in vitro model of human brain development. We have developed a human pluripotent stem cell-derived 3D organoid culture system, termed cerebral organoid, which develops various discrete though interdependent brain regions. These include cerebral cortex containing progenitor populations that organize and produce mature cortical neuron subtypes. Furthermore, cerebral organoids recapitulate features of human cortical development, namely characteristic progenitor zone organization with abundant outer radial glial stem cells. Finally, we use RNAi and patient-specific iPS cells to model microcephaly, a disorder that has been difficult to recapitulate in mice. We demonstrate premature neuronal differentiation in patient organoids, a defect that could explain the disease phenotype. Our data demonstrate that 3D organoids can recapitulate development and disease of even this most complex human tissue.

Retrograde interferon‐gamma signaling induces major histocompatibility class I expression in human‐induced pluripotent stem cell‐derived neurons

“…Previously it was shown that high‐density NSC cultures spontaneously form neural aggregates that recapitulate several NSC niche components 37. In line with this, large neural aggregates or neural organoids exhibiting CNS tissue architecture have recently been described 38, 39. It has also been proposed that MICs could offer further benefits for culturing NSCs and NSC‐derived cells.…”

Translational potential of human brain organoids

“…Building on these earlier works, a recent flurry of papers described the generation of various neural organoids (Table 1), ranging from the whole‐brain organoids,27, 28, 29 to large sub‐brain regions such as cortical organoids,30, 31 to specific regions, including cerebellum,32 midbrain,33 adenohypophysis,34 hypothalamus,35 and hippocampus 36. Comparing with the classical neurospheres, these organoids are generally much larger.…”

“…In addition to the increased size, cerebral organoids showed highly thickened neuronal lobes within which neural progenitors and neurons reside. Immunostaining analysis revealed the presence of distinct zones such as the ventricular zone (VZ), the intermediate zone (IZ), and even the cortical plate‐like structure, similar to the developing brain 27, 29. Particularly exciting is the presence of so‐called outer subventricular zone (oSVZ), an embryonic structure that is uniquely expanded in humans but absent in rodents.…”

“…Loss‐of‐function mutation in CDK5RAP2 has been implicated in microcephaly, but mouse models failed to reproduce the full spectrum of human phenotypes 39, 40. When brain organoids were generated from microcephaly patients harboring truncating mutations of CDK5RAP2 , they were found to be significantly smaller than the ones generated from controls 27. The authors went on to show that precocious neuronal differentiation likely contributed to the overall smaller dimensions of the patient‐derived organoids 27.…”

A Modular Assembly of Spinal Cord–Like Tissue Allows Targeted Tissue Repair in the Transected Spinal Cord

“…The recent development of stem cell–based tissue engineering technology has provided a promising strategy for treating SCI 4. With the insights gained from developmental biology and the advancement in 3D culturing, tissue engineering has entered a new era of constructing of multiple tissue types or organoids 5. It is believed that tissue engineering would help realize constructing a functional tissue or organoid through the combination of stem cells, functional biomaterials, and neurotrophic factors to treat diseases of the central nervous system, including SCI 6…”