Differentiation of hypothalamic-like neurons from human pluripotent stem cells

Wang, Liheng; Meece, Kana; Williams, Damian J.; Lo, Kinyui Alice; Zimmer, Matthew; Heinrich, Garrett; Carli, Jayne Martin; LeDuc, Charles A.; Sun, Lei; Zeltser, Lori M.; Freeby, Matthew; Goland, Robin; Tsang, Stephen H.; Wardlaw, Sharon L.; Egli, Dieter; Leibel, Rudolph L.

doi:10.1172/jci79220

Cited by 118 publications

(135 citation statements)

References 61 publications

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“…The cerebral organoid offers an opportunity to model whole brain development and interactions among different brain regions. Brain region-specific organoids, by contrast, use patterning factors to induce the differentiation of hPSCs into specific lineages, such as cerebral cortex (Kadoshima et al, 2013;Mariani et al, 2015;Pasça et al, 2015;Qian et al, 2016), midbrain (Jo et al, 2016;Qian et al, 2016) and hypothalamus (Merkle et al, 2015;Qian et al, 2016;Sakaguchi et al, 2015;Wang et al, 2015). Compared with cerebral organoids, brain region-specific organoids model individual brain regions of interest and generally result in more uniform and reproducible tissue, providing a platform for quantitative characterization.…”

Section: Why Use Brain Organoids?mentioning

confidence: 99%

Using brain organoids to understand Zika virus-induced microcephaly

et al. 2017

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Technologies to differentiate human pluripotent stem cells into threedimensional organized structures that resemble in vivo organs are pushing the frontiers of human disease modeling and drug development. In response to the global health emergency posed by the Zika virus (ZIKV) outbreak, brain organoids engineered to mimic the developing human fetal brain have been employed to model ZIKV-induced microcephaly. Here, we discuss the advantages of brain organoids over other model systems to study development and highlight recent advances in understanding ZIKV pathophysiology and its underlying pathogenesis mechanisms. We further discuss perspectives on overcoming limitations of current organoid systems for their future use in ZIKV research.

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Section: Why Use Brain Organoids?mentioning

confidence: 99%

Using brain organoids to understand Zika virus-induced microcephaly

et al. 2017

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“…S7), suggesting that the protocol could be modified to more efficiently produce dorsal or anterior hypothalamic cell types. Indeed, a recent study suggests that activation the SHH pathway followed by inhibition of the NOTCH pathway enables the generation of hypothalamic neuron types typically found in the arcuate nucleus (Wang et al, 2015). Finally, the two-dimensional nature of the protocol is easily scalable, making it an attractive option for applications that require large numbers of neurons, such as drug screening or disease modeling.…”

Section: Comparison Of Hypothalamic Differentiation Strategiesmentioning

confidence: 99%

Generation of neuropeptidergic hypothalamic neurons from human pluripotent stem cells

et al. 2015

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Hypothalamic neurons orchestrate many essential physiological and behavioral processes via secreted neuropeptides, and are relevant to human diseases such as obesity, narcolepsy and infertility. We report the differentiation of human pluripotent stem cells into many of the major types of neuropeptidergic hypothalamic neurons, including those producing pro-opiolemelanocortin, agoutirelated peptide, hypocretin/orexin, melanin-concentrating hormone, oxytocin, arginine vasopressin, corticotropin-releasing hormone (CRH) or thyrotropin-releasing hormone. Hypothalamic neurons can be generated using a 'self-patterning' strategy that yields a broad array of cell types, or via a more reproducible directed differentiation approach. Stem cell-derived human hypothalamic neurons share characteristic morphological properties and gene expression patterns with their counterparts in vivo, and are able to integrate into the mouse brain. These neurons could form the basis of cellular models, chemical screens or cellular therapies to study and treat common human diseases.

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“…Moreover, further treatment of the re-aggregated cells with SHH induces efficient differentiation of other types of hypothalamic neurons (Wataya et al 2008;Merkle et al 2015). Very recently, human ESC and iPSC were used to generate hypothalamic neurons in aggregates (Merkle et al 2015;Wang et al 2015), following the previously dribed protocol (Wataya et al 2008). Hypothalamic neurons were successfully obtained, but important differences were noted.…”

Section: Induction Of Hypothalamic Identity From 3d Esc Aggregatesmentioning

confidence: 99%

“…Hypothalamic neurons were successfully obtained, but important differences were noted. These included the requirement for insulin for initial aggregate survival, along with an Akt inhibitor (Merkle et al 2015), whereas Wang et al (2015) used SMAD inhibitors to inactivate BMP and TGβ/Nodal/Activin pathways to promote neural differentiation. The major types of hypothalamic neurons were obtained, and further culturing with supporting mouse glia showed that these adopted morphologies similar to their in vivo counterpart, suggesting a mature phenotype.…”

Section: Induction Of Hypothalamic Identity From 3d Esc Aggregatesmentioning

confidence: 99%

“…Recently, populations of AdSCs have been described and partially characterized in both compartments of the axis (Lee et al 2012;Li et al 2012;Andoniadou et al 2013;Haan et al 2013;Rizzoti et al 2013;Robins et al 2013a, b;Castinetti et al 2011) and their characterization will be presented here, with reference to other chapters of this book. Finally, exciting progress has been made toward the use of stem cells for regenerative medicine in the axis: both hypothalamic neurons (Wataya et al 2008;Merkle et al 2015;Wang et al 2015) and pituitary endocrine cells (Suga et al 2011;Dincer et al 2013) have been obtained in vitro from stem cells and successfully transplanted in mice. We will discuss these reports and the future challenges toward clinical use of stem cells in the hypothalamo-pituitary axis.…”

Section: Introductionmentioning

confidence: 99%

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Perspective on Stem Cells in Developmental Biology, with Special Reference to Neuroendocrine Systems

Rizzoti

Pires

Lovell‐Badge

2016

Stem Cells in Neuroendocrinology

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In the embryo, organs gradually take shape as tissue progenitors, proliferate, differentiate and are organised, via cellular interactions, in tri-dimensional functional structures. Most adult organs retain a cell population sharing important similarities with embryonic progenitors, which includes the ability to both selfrenew and to differentiate into the full range of the specialised cell types corresponding to the organ in which they reside. These two essential properties define them as adult stem cells (AdSC). Their characterization in different contexts provides a better understanding of cell turnover modalities for organ function, which is important for tumorigenesis, because adult tissue stem cells can give rise to cancer stem cells. However, it is also relevant to regenerative medicine, because stem cells can be transplanted or manipulated in vivo to restore missing cells. The successful reprogramming of somatic cells into induced pluripotent stem cells (iPSC) (Takahashi and Yamanaka, Cell 126:663-676, 2006), resembling pluripotent embryonic stem cells (ESC), opened alternative strategies for cell replacement. The required cell type can be differentiated in vitro from expandable progenitors and transplanted where required. This approach is particularly promising, because genetic defects can potentially be repaired in vitro prior to their engraftment; moreover, a large number of cells can be produced (Fox et al., Science 345:1247391, 2014). However, the transplanted cells have to be able to functionally integrate into the deficient organ. To potentially alleviate this problem, tri-dimensional culture systems have been recently developed where mini-organs, or organoids, can be obtained in vitro. These also represent unique models for disease modelling and drug screening (Huch and Koo, Development 142:3113-3125, 2015). Within neuroendocrine systems, the hypothalamo-pituitary axis has a crucial role for body homeostasis. It also regulates functions such as growth, reproduction, stress and, more generally, metabolism. The hypothalamus centralizes information from the periphery and other brain regions to regulate pituitary hormone secretions and to control appetite, sleep and aging. Its functions are exerted through secretion of neurohormones and manipulation of these could be of interest not only for the treatment of obesity and sleep disorders but also to alleviate aging-related conditions. Pituitary hormone deficiencies can originate from defects affecting the hypothalamus, pituitary, or both. Today these deficiencies are treated by substitution or replacement therapies, which are costly and have side effects. AdSC have recently been characterized in the hypothalamus and pituitary (Castinetti et al., Endocr Rev 32:453-471, 2011; Bolborea and Dale, Trends Neurosci 36:91-100, 2013). Moreover, hypothalamic neurons and pituitary endocrine cells have been differentiated in vitro from ESC and iPSC and successfully transplanted. These promising routes for development of regenerative medicine to restore ...

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Differentiation of hypothalamic-like neurons from human pluripotent stem cells

Cited by 118 publications

References 61 publications

Using brain organoids to understand Zika virus-induced microcephaly

Using brain organoids to understand Zika virus-induced microcephaly

Generation of neuropeptidergic hypothalamic neurons from human pluripotent stem cells

Perspective on Stem Cells in Developmental Biology, with Special Reference to Neuroendocrine Systems

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