Publications

A huge challenge in understanding human early embryo cell fate is due to limited access and ethical concerns. Recent research, however, from José C. R. Silva’s lab at Guangzhou National Laboratory, drawing from single-cell sequencing, suggests a conserved lineage specification process between human and mouse embryos. Blastoids, emerging models for early embryo development, generated solely from hnPSCs, offer insights into blastocyst formation without altering culture conditions. Self-renewing human naïve pluripotent stem cells (hnPSCs) spontaneously form blastoids in 3D culture, mimicking early human blastocysts. This process, mediated by the GSK3 inhibitor IM-12 in 5iLAF medium, involves upregulation of oxidative phosphorylation genes. hnPSCs dedifferentiate into E5 embryo-like intermediates, expressing SOX2/OCT4 and GATA6, which specify trophoblast fate by day 3, coinciding with blastoid formation. This was a fantastic paper to read as it is clear how this spontaneous blastoid formation highlights the importance of culture conditions and provides a new platform to study human embryo development in vitro, potentially reshaping our understanding of hnPSCs and embryo development.

Cell therapy is becoming a possibility for many previously untreatable conditions, and it should be accessible to everyone. Creating a cost-effective, reliable and reproducible way of culturing human induced pluripotent stem cells (hiPSCs) in a range of research labs, and allowing large scale culture for gene-editing purposes takes us one step closer to this.

Using high potency thermostable Qkine 145 amino acid FGF-G3 reduce FGF-2 use 8-fold and for weekend-free culture reduced media use by 57%. This makes hiPSCs a more accessible model for many labs doing basic and translational research.

Read summary blog

It has been a pleasure to read about the intricate dance of signaling coordination between the epiblast, trophectoderm, and hypoblast during early human embryonic development in this recent publication from the lab of Magdalena Zernicka-Goetz at the California Institute of Technology/University of Cambridge. Using human embryos and stem cell models, the research reveals NODAL dependency in anterior hypoblast specification, contrasting roles of BMP in mouse and human anterior signaling center maintenance, and the importance of NOTCH signaling in human epiblast survival. Comparative analysis highlights conserved and species-specific factors driving embryonic development. Specifically, NODAL, BMP, and NOTCH play crucial roles in anterior hypoblast formation, with signaling dynamics changing significantly post-implantation. The fantastic research underscores the complexity of signaling pathways during implantation and emphasizes the importance of further investigations to elucidate their roles comprehensively. These findings clearly contribute to understanding early human embryonic development and provide insights for improving stem cell-derived embryo-like models.

In the study of embryonic stem cells, stem cells representative of naïve and primed pluripotency have been well established in the forms of embryonic stem cells (ESCs) and epiblast-derived stem cells (EpiSCs). In this study Kinoshita et al. fill the gap between early and late pluripotency in describing an intermediate state; formative stem (FS) cells. FS cells differ from both ESCs and EpiSCs, a difference beautifully exemplified by their relative contribution to chimeras. Compared with ESCs, which readily contribute to chimeras, FS chimera contribution is less frequent, and their contribution is less evenly distributed. EpiSCs on the other hand do not generally contribute to chimeras at all. FS cells were established by culturing E5.5 epiblasts, or ES cells, in N2B27 media supplemented with a low dose of Qkine Activin A alongside a Wnt inhibitor and pan-retinoic acid receptor inverse agonist. We are proud our growth factors could be part of such an exciting finding!

In embryonic development, growth factors are delivered in a highly controlled and targeted manner, however when differentiating iPSCs the real challenge is to effectively mimic these conditions. Consequently, iPSC differentiation is plagued by issues such as low efficiency and a lack of homogeneity. In their recent paper Andreasson et al. take a step towards improving the differentiation of iPSCs to definitive endoderm. The group employs gold nanoparticles to generate a gradient of immobilised Activin A – a member of the TGF-β superfamily that plays a key role in definitive endoderm development. Using this gradient, the group was able to deliver Activin A in a controlled and localised manor, resulting in more efficient differentiation. By deploying their innovative approach, the group observed a dose dependent response of the cells to Activin A, as defined by expression of differentiation markers SOX17 and GATA4. Their results indicate that it may be possible to define an optimal density of Activin A for definitive endoderm differentiation – a finding that could improve the homogeneity and speed of differentiation. This innovative study is a wonderful example of how reconsidering the way in which growth factors are delivered can lead to advances in our understanding of the precise control of stem cell differentiation and how these cells undertake their fate decisions.

Macarelli et al demonstrate the importance of using the right cells and tools for the study of neural stem cell models in this recent publication. They explored the use of different ciliary targeting sequences to fluorescently label and measure cilia. This allows the study of the structure and function of these important sensory and signaling structures in differentiated neural cells. An exciting addition to the knowledge of tools to study neural differentiation from the lab of Dr Florian Merkle at the Cambridge Stem Cell Institute.

We all know our stem cell cultures are sensitive and high maintenance, we feed them, keep them warm to make sure we get the most accurate, reproducible data. The composition of their media is important, we need the right growth factors, but this week’s Friday read highlights that their exposure to oxygen can be an important factor in the differentiation and function of cellular models. In this very interesting read from the MRC Institute of Metabolic Science they have investigated the impact of oxygen diffusion and media volume on hypoxia-related transcriptional changes in stem cell cultures. They found that decreasing the media volume decreased lactate production and HIF1α expression and increased the functionality of adipocyte, hiPSC-derived hepatocytes and hiPSC-derived cardiac organoid cultures.

Cell therapy is becoming a possibility for many previously untreatable conditions, and it should be accessible to everyone. Creating a cost-effective, reliable and reproducible way of culturing human induced pluripotent stem cells (hiPSCs) in a range of research labs, and allowing large scale culture for gene-editing purposes takes us one step closer to this.

Using high potency thermostable Qkine 145 amino acid FGF-G3 reduce FGF-2 use 8-fold and for weekend-free culture reduced media use by 57%. This makes hiPSCs a more accessible model for many labs doing basic and translational research.

Read summary blog

Cell therapy is becoming a possibility for many previously untreatable conditions, and it should be accessible to everyone. Creating a cost-effective, reliable and reproducible way of culturing human induced pluripotent stem cells (hiPSCs) in a range of research labs, and allowing large scale culture for gene-editing purposes takes us one step closer to this.

Using high potency thermostable Qkine 145 amino acid FGF-G3 reduce FGF-2 use 8-fold and for weekend-free culture reduced media use by 57%. This makes hiPSCs a more accessible model for many labs doing basic and translational research.

Read summary blog

Robert Thomas’s lab at Loughborough University has analyzed growth dynamics between commonly occurring genetically variant hPSCs and their counterpart wild-type cells in culture cells using proprietary computational modelling, allowing the identification of critical process parameters that drive critical quality attributes when genetically variant cells are present within the system This fascinating paper highlights how the system parameters controlling independent growth behavior of wild-type and genetic variant populations are altered when both populations exist within a co-culture environment by introducing an ordinary differential equation (ODE) framework. Findings reveal that variant cells exhibit selective growth and competitive advantage, influencing the behavior of wild-type cells, particularly at higher culture densities. This computational model offers opportunities for defining operational protocols and timely detection of emerging variants, crucial for product release and risk management. It is clear to see the importance as it demonstrates the utility of computational models in understanding complex biological systems and informing manufacturing practices in hPSC-based therapies.

We all know our stem cell cultures are sensitive and high maintenance, we feed them, keep them warm to make sure we get the most accurate, reproducible data. The composition of their media is important, we need the right growth factors, but this week’s Friday read highlights that their exposure to oxygen can be an important factor in the differentiation and function of cellular models. In this very interesting read from the MRC Institute of Metabolic Science they have investigated the impact of oxygen diffusion and media volume on hypoxia-related transcriptional changes in stem cell cultures. They found that decreasing the media volume decreased lactate production and HIF1α expression and increased the functionality of adipocyte, hiPSC-derived hepatocytes and hiPSC-derived cardiac organoid cultures.

The drug discovery process is reliant on appropriate models for high-throughput screening, this can be difficult when complex, heterogeneous diseases are the targeted indication. This publication reports on a fascinating zebrafish model for the study of medulloblastoma, one of the most common malignant brain tumors in children. Introduction of medulloblastoma cells into zebrafish embryos leads to tumor growth in the hindbrain region and the homing of transplanted cells and the aggressiveness of tumor growth were enhanced by pre-culturing cells in a neural stem cell-like medium. This model was then used to successfully assess the effect of anti-cancer drugs on the viability of medulloblastoma cells in this zebrafish embryo model.

The recent publication from Fejzo et al. discusses the role of GDF-15, an intriguing protein acting on the brainstem, in nausea and vomiting during pregnancy, particularly in hyperemesis gravidarum (HG). This study finds that both fetal production of GDF-15 and maternal sensitivity to GDF-15 significantly contribute to the risk of HG with higher levels of GDF15 in maternal blood associated with vomiting during pregnancy and HG. Genetic variants affecting GDF-15 levels influence the risk of HG, with low levels increasing the risk and high levels decreasing it. This was an excellent read which suggests a putative causal role for fetally derived GDF-15 in pregnancy-related nausea and vomiting, with maternal sensitivity influenced by pre-pregnancy exposure and shows great promise for potential avenues of treatment and prevention of HG by blocking GDF-15 action in the pregnant mother.

In this paper, Cinimo et al. explore the role of the TGFβ-family protein GDF15 in activation of the hypothalamic–pituitary–adrenal (HPA) axis. During infection, cytokines such as TNFα/β, IL-1 and IL-6, activate the HPA axis. This increases circulating glucocorticoids, which have anti-inflammatory, metabolic, and vasomotor effects. However, O’Rahilly lab have determined that in response to stimuli such as toxins, which don’t provoke an inflammatory response, the primary activator of the HPA axis is GDF15. GDF15 is an intriguing protein also being explored as an anti-obesity therapeutic target, these findings may have a pivotal impact on future clinical study design and open new avenues of investigation. Certainly cool science!

A huge challenge in understanding human early embryo cell fate is due to limited access and ethical concerns. Recent research, however, from José C. R. Silva’s lab at Guangzhou National Laboratory, drawing from single-cell sequencing, suggests a conserved lineage specification process between human and mouse embryos. Blastoids, emerging models for early embryo development, generated solely from hnPSCs, offer insights into blastocyst formation without altering culture conditions. Self-renewing human naïve pluripotent stem cells (hnPSCs) spontaneously form blastoids in 3D culture, mimicking early human blastocysts. This process, mediated by the GSK3 inhibitor IM-12 in 5iLAF medium, involves upregulation of oxidative phosphorylation genes. hnPSCs dedifferentiate into E5 embryo-like intermediates, expressing SOX2/OCT4 and GATA6, which specify trophoblast fate by day 3, coinciding with blastoid formation. This was a fantastic paper to read as it is clear how this spontaneous blastoid formation highlights the importance of culture conditions and provides a new platform to study human embryo development in vitro, potentially reshaping our understanding of hnPSCs and embryo development.

Generating cell types with properties of embryo cells with full developmental potential is of great biological importance. This paper describe steps for induction and isolation of MLCs by sorting. They explained the procedures for segregating MLCs into blastocyst cell fates and how to create embryo-like structures from them. This system provides a valuable stem-cell-based embryo model to study early embryo development.

This paper gives us insight into the complex regulatory interactions between BMP-4 and noggin during neural tube development. Neural tube organoids from embryonic stem cells will organize into floorplates, without the usual inducers present in the developing embryo. They used mouse neural tube organoids and by identifying the floorplate marker FOXA2 they showed the importance of regulation of BMP-4 signaling through noggin. Noggin mutation reduced neural tube organization and floorplate formation in vitro and in vivo.

A promising application of organoids, in this case patient-derived organoids (PDOs), is to profile the therapeutic sensitivity of tumors to inform clinical decisions and to stratify patients in clinical trials more effectively. Recently there have been positive results from clinical trials giving a glimmer of the potential impact of these technologies. However, a concern is how reproducible these technologies are, particularly as most still rely on animal-derived basement membrane extracts, where batch variation is a sector-wide concern. This recent publication shows consistent drug responses are observed when different sources of commercial BME were compared. This is reassuring and speaks to how robust these approaches can be.

Cell therapy is becoming a possibility for many previously untreatable conditions, and it should be accessible to everyone. Creating a cost-effective, reliable and reproducible way of culturing human induced pluripotent stem cells (hiPSCs) in a range of research labs, and allowing large scale culture for gene-editing purposes takes us one step closer to this.

Using high potency thermostable Qkine 145 amino acid FGF-G3 reduce FGF-2 use 8-fold and for weekend-free culture reduced media use by 57%. This makes hiPSCs a more accessible model for many labs doing basic and translational research.

Read summary blog

A promising application of organoids, in this case patient-derived organoids (PDOs), is to profile the therapeutic sensitivity of tumors to inform clinical decisions and to stratify patients in clinical trials more effectively. Recently there have been positive results from clinical trials giving a glimmer of the potential impact of these technologies. However, a concern is how reproducible these technologies are, particularly as most still rely on animal-derived basement membrane extracts, where batch variation is a sector-wide concern. This recent publication shows consistent drug responses are observed when different sources of commercial BME were compared. This is reassuring and speaks to how robust these approaches can be.

This recent study from David Shin in the lab of Tomasz J. Nowakowski University of California, explores thalamic dysfunction in psychiatric disorders, focusing on the 22q11.2 microdeletion associated with increased risk. They used human pluripotent stem cell-derived organoids to investigate early thalamus development, revealing widespread transcriptional dysregulation and elevated FOXP2 expression in thalamic neurons and glia. From a co-culture model, they found that the microdeletion leads to thalamic axon overgrowth, mediated by FOXP2. These findings suggest dysregulated thalamic development contributes to schizophrenia-related neural phenotypes in 22q11.2 deletion syndrome, offering fascinating insights into the neuropsychiatric disorder’s genetic mechanisms. It will be very interesting to see how human pluripotent stem cell-derived organoids continue to play a fundamental role in psychiatric disorders in the future!

Cell therapy is becoming a possibility for many previously untreatable conditions, and it should be accessible to everyone. Creating a cost-effective, reliable and reproducible way of culturing human induced pluripotent stem cells (hiPSCs) in a range of research labs, and allowing large scale culture for gene-editing purposes takes us one step closer to this.

Using high potency thermostable Qkine 145 amino acid FGF-G3 reduce FGF-2 use 8-fold and for weekend-free culture reduced media use by 57%. This makes hiPSCs a more accessible model for many labs doing basic and translational research.

Read summary blog

Robert Thomas’s lab at Loughborough University has analyzed growth dynamics between commonly occurring genetically variant hPSCs and their counterpart wild-type cells in culture cells using proprietary computational modelling, allowing the identification of critical process parameters that drive critical quality attributes when genetically variant cells are present within the system This fascinating paper highlights how the system parameters controlling independent growth behavior of wild-type and genetic variant populations are altered when both populations exist within a co-culture environment by introducing an ordinary differential equation (ODE) framework. Findings reveal that variant cells exhibit selective growth and competitive advantage, influencing the behavior of wild-type cells, particularly at higher culture densities. This computational model offers opportunities for defining operational protocols and timely detection of emerging variants, crucial for product release and risk management. It is clear to see the importance as it demonstrates the utility of computational models in understanding complex biological systems and informing manufacturing practices in hPSC-based therapies.