GSK3β Inhibition Promotes Efficient Myeloid and Lymphoid Hematopoiesis from Non-human Primate-Induced Pluripotent Stem Cells

D'Souza, Saritha S.; Maufort, John P.; Kumar, Akhilesh; Zhang, Jiuchun; Smuga-Otto, Kimberley; Thomson, James A.; Slukvin, Igor I.

doi:10.1016/j.stemcr.2015.12.010

Cited by 34 publications

(44 citation statements)

References 44 publications

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“…Notwithstanding their limitations, it is important to continue to use model organisms, which remain virtually unrestricted resources in which to pursue detailed analyses of HSC development. Although not free from ethical and practical considerations, research using nonhuman primates may also provide valuable information that will help to bridge the evolutionary gap between the mouse and human (D'Souza et al, 2016).…”

Section: Future Directions and Challengesmentioning

confidence: 99%

Human haematopoietic stem cell development: from the embryo to the dish

et al. 2017

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Haematopoietic stem cells (HSCs) emerge during embryogenesis and give rise to the adult haematopoietic system. Understanding how early haematopoietic development occurs is of fundamental importance for basic biology and medical sciences, but our knowledge is still limited compared with what we know of adult HSCs and their microenvironment. This is particularly true for human haematopoiesis, and is reflected in our current inability to recapitulate the development of HSCs from pluripotent stem cells in vitro. In this Review, we discuss what is known of human haematopoietic development: the anatomical sites at which it occurs, the different temporal waves of haematopoiesis, the emergence of the first HSCs and the signalling landscape of the haematopoietic niche. We also discuss the extent to which in vitro differentiation of human pluripotent stem cells recapitulates bona fide human developmental haematopoiesis, and outline some future directions in the field.

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Section: Future Directions and Challengesmentioning

confidence: 99%

Human haematopoietic stem cell development: from the embryo to the dish

et al. 2017

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“…To ensure a reproducible and robust differentiation approach, we made use of a feeder-free culture system15 in combination with chemically defined differentiation conditions. This is in contrast to reported differentiation methods for NHP pluripotent stem cells, which generally use stem cell culture on feeder cells and differentiation methods based on parameters with high variability, such as embryoid body formation or the addition of serum needed for OP9 co-cultures17262728.…”

Section: Discussionmentioning

confidence: 85%

Establishment of a translational endothelial cell model using directed differentiation of induced pluripotent stem cells from Cynomolgus monkey

Thoma

Heckel

Keller

et al. 2016

Sci Rep

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Due to their broad differentiation potential, pluripotent stem cells (PSCs) offer a promising approach for generating relevant cellular models for various applications. While human PSC-based cellular models are already advanced, similar systems for non-human primates (NHPs) are still lacking. However, as NHPs are the most appropriate animals for evaluating the safety of many novel pharmaceuticals, the availability of in vitro systems would be extremely useful to bridge the gap between cellular and animal models. Here, we present a NHP in vitro endothelial cell system using induced pluripotent stem cells (IPSCs) from Cynomolgus monkey (Macaca fascicularis). Based on an adapted protocol for human IPSCs, we directly differentiated macaque IPSCs into endothelial cells under chemically defined conditions. The resulting endothelial cells can be enriched using immuno-magnetic cell sorting and display endothelial marker expression and function. RNA sequencing revealed that the differentiation process closely resembled vasculogenesis. Moreover, we showed that endothelial cells derived from macaque and human IPSCs are highly similar with respect to gene expression patterns and key endothelial functions, such as inflammatory responses. These data demonstrate the power of IPSC differentiation technology to generate defined cell types for use as translational in vitro models to compare cell type-specific responses across species.

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“…We demonstrate the ability of these lithium-treated ESCs to further derive into HSCs after defined maturation and confirm the endothelialto-hematopoietic transition. Since β-catenin-mediated mechanisms for HSC development are conserved in human and mouse species 5,8,13 our results demonstrate a novel strategy for generating efficiently HSCs in vitro as a multipotent source of stem cells to be used in a variety of blood and muscular biomedical applications.…”

Section: Introductionmentioning

confidence: 84%

“…Previous studies have shown that GSK3β inhibition induces HE development from ESCs 5,8 . We next studied whether continued exposure to 2 and 10 mM Li + drives ESC differentiation into HE after 6 days of culture.…”

Section: High Concentrations Of LI + Promote Esc Differentiation Intomentioning

confidence: 95%

“…Previous studies on CHIR99021 have shown that this pharmacological GSK3 inhibitor is capable of stabilizing β-catenin and promoting its transcriptional activity 6,7 and thus inducing HE formation. The activation of the Wnt pathway by inhibiting GSK3 using CHIR99021 in the first stages of ESC differentiation followed by stimulation of the vascular endothelial growth factor (VEGF) further induces the differentiation of PSCs to HE and subsequently to HSCs 8 . Lithium is another welldefined GSK3 inhibitor and has been used for the treatment of bipolar disorder for decades 9 .…”

Section: Introductionmentioning

confidence: 99%

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Lithium directs embryonic stem cell differentiation versus hemogenic endothelium

Mnatsakanyan

Salmerón-Sánchez

Rico

2020

Preprint

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The discovery that the definitive hematopoietic stem cells (HSCs) derive from specialized regions of the endothelium, known as the hemogenic endothelium (HE), shed a good deal of light on HSC embryonic developmental processes. This knowledge opened up new possibilities for the design of new strategies to obtain HSCs in vitro from pluripotent stem cells (PSCs). Previous advances in this field have shown that the Wnt/β-catenin signaling pathway plays a key role in PSC-derived HSC formation. In this work, we identified lithium, a GSK3 inhibitor, as an element capable of stabilizing β-catenin and inducing ESC differentiation in the mesoderm lineage and subsequently in the HE, highly consistent with the role of Wnt agonists on ESC differentiation. ESCs treated with 10 mM lithium express CD31+, Sca-1+, Nkx2-5+ and Runx1+ cells characteristic of HE cells. The ability of lithium-treated ESCs to further derive into HSCs was confirmed after defined maturation, resulting in rounded cell aggregates positive for fetal and mature HSCs markers, confirming the endothelial to hematopoietic transition. Our results represent a novel strategy for generating HSC in vitro as a multipotent source of stem cells for blood and muscle disease therapies.

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GSK3β Inhibition Promotes Efficient Myeloid and Lymphoid Hematopoiesis from Non-human Primate-Induced Pluripotent Stem Cells

Cited by 34 publications

References 44 publications

Human haematopoietic stem cell development: from the embryo to the dish

Human haematopoietic stem cell development: from the embryo to the dish

Establishment of a translational endothelial cell model using directed differentiation of induced pluripotent stem cells from Cynomolgus monkey

Lithium directs embryonic stem cell differentiation versus hemogenic endothelium

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