Is this a brain which I see before me? Modeling human neural development with pluripotent stem cells

Abstract

The human brain is arguably the most complex structure among living organisms. However, the specific mechanisms leading to this complexity remain incompletely understood, primarily because of the poor experimental accessibility of the human embryonic brain. Over recent years, technologies based on pluripotent stem cells (PSCs) have been developed to generate neural cells of various types. While the translational potential of PSC technologies for disease modeling and/or cell replacement therapies is usually put forward as a rationale for their utility, they are also opening novel windows for direct observation and experimentation of the basic mechanisms of human brain development. PSC-based studies have revealed that a number of cardinal features of neural ontogenesis are remarkably conserved in human models, which can be studied in a reductionist fashion. They have also revealed species-specific features, which constitute attractive lines of investigation to elucidate the mechanisms underlying the development of the human brain, and its link with evolution.

DNA Methylation Dynamics in Neurogenesis

“…The basic features of cortical neurogenesis appear to be well-conserved among mammals; however, a number of human-specific features have been identified as well [22]. For example, during human cortical neurogenesis, there is an extended period of initial amplification of NEs followed by a much protracted period of generation of neurons from progenitors, allowing the generation of a much larger number of neurons as compared with rodent [23].…”

Neural patterning of human induced pluripotent stem cells in 3-D cultures for studying biomolecule-directed differential cellular responses

“…Neural patterning in 3-D differentiation from hPSCs in vitro aims to mimic in vivo regional patterning of human brain [6]. SHH signaling that patterns ventral part of neural tube in vivo has been used to derive a specific neuronal cell type in vitro in combination with several other signaling pathways, such as Wnt, RA, and FGF-2 [14].…”

“…Human induced pluripotent stem cells (hiPSCs) can generate allogeneic or patient-specific neural cells, cortical tissues, and even mini-brains (i.e., brain organoids), which are physiologically relevant to model neural diseases and to identify pharmacological therapeutics [2][3][4][5][6][7]. While some disease progressions (e.g., amyloid-β plaques) may take years, in vitro neural models derived from hiPSCs can be used to probe disease on-set and development in a shortened time frame [8].…”

“…Thus, differential levels of SHH signaling, in combination with other signaling such as Wnt and retinoic acid, influence neural regional specification of hPSCs into forebrain cortical tissues, midbrain tissues, and hindbrain/spinal cord tissues [6]. In biomaterials research, one attractive approach is to modulate hPSC fate decisions and differentiations using small molecules that regulate signaling pathways through defined mechanisms [26][27][28][29].…”

Wnt-YAP interactions in the neural fate of human pluripotent stem cells and the implications for neural organoid formation

“…9 Wnt signaling can switch rostral and caudal brain tissue identity in human neural tissue morphogenesis in a concentration-dependent manner. 10 In the meanwhile, Hippo/Yes-associated protein (YAP) signaling has been identified as another important pathway that plays a critical role in organ growth control as well as stem cell propagation and differentiation. 11 The interactions of Wnt signaling and YAP expression attract extensive interests in regenerative medicine recently, 12,13 but how Wnt-YAP interactions affect neural tissue morphogenesis from hPSCs has been unexplored.…”