Kirkeby Lab

Human Neural Development group

The Kirkeby group studies the factors involved in human neural subtype specification in order to enable production of specific neurons for understanding and treating neurological diseases.

Agnete Kirkeby info

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Creating a human fetal brain in the dish with microfluidics (the MiSTR model)

This project is an interdisciplinary collaboration joining forces from the fields of bioengineering and stem cell biology with the aim of producing a novel model of early human neural tube patterning. Through microfluidic engineering techniques, we expose hESCs to morphogenic gradients in vitro, thereby building a microenvironment in which the stem cells are patterned into structures resembling the early stages of the rostral-to-caudal regionalised human neural tube. With this technique, we produce an anatomically relevant 3D in vitro model of the developing human neural tube corresponding to around weeks 2-10 of fetal development – read more here.

Mapping human neural subtype identities through single cell RNAseq

Using the MiSTR model described above, we apply single cell RNA sequencing to map the complexity of human neural subtypes present during early and late neural specification. By mapping cells at a single cell level at several different time points, we identify the unique molecular signatures of different human neural subtypes and aim to dissect the trajectories underlying the regionalisation and subregionalisation of human neural progenitors and neurons during embryo development.

Identifying secreted factors from different human brain regions through proteomics

For this project, we use our MISTR model to search for human-specific patterns of developmental growth factors through unbiased mass-spec (MS) proteomic analysis of the secreted proteins produced from different neural regions during development. Novel candidates identified from this approach are explored for their biological function in directing neural cells towards specific neuronal subtypes and for inducing neuronal subtype maturation.

Studying the functions of long non-coding RNAs in human neural cells

Long non-coding RNAs (lncRNAs) are highly abundant in the human genome, and for the vast majority of these their functions are unknown. Here, we apply CRISPR gene editing techniques in human pluripotent cells (CRISPR knockout, CRISPR activation and CRISPR inhibition) to investigate the functions of novel lncRNAs during human neural specification and differentiation. We aim to uncover both general functions in neural differentiation as well as more specific functions in regional subtype specification.

Generating human hypothalamic neurons for studying neuronal control of appetite and metabolism

The hypothalamus is important for regulating appetite, metabolism and sleep, and hypothalamic neuronal dysfunction is coupled to obesity, type 2 diabetes and narcolepsy. As such, access to functional human hypothalamic neurons is of great interest to pharma, biotech and academia for use in disease modelling, drug screening and cell replacement therapies. However, protocols for generation of subtype-specific hypothalamic neurons are still suboptimal, partly due to a lack of knowledge on the developmental trajectories giving rise to each specific neuronal subtype of the hypothalamus. In this project, we generate protocols for subtype-specific differentiation of hESCs into different subregions of the hypothalamus, and we investigate the neuronal lineages through single cell RNA sequencing. We focus in particular on hypothalamic neuronal subtypes which are important for the regulation of appetite, metabolism and sleep

Generating human hypocretin (HCRT) neurons for treatment of narcolepsy

Narcolepsy is a chronic, neurological disease affecting approximately 20-50 out of 100,000 individuals. The disease onset is typically during adolescence or early adulthood, and symptoms include excessive daytime sleepiness, cataplexy, hypnagogic hallucinations and sleep paralysis. The most common form of the disease, Type 1 narcolepsy, is caused by the selective loss of HCRT neurons in the hypothalamus of the patients. In this project, we generate protocols for production of HCRT neurons from hESCs, and we investigate in animal models the potential of these neurons to be used as a transplantation therapy for narcolepsy, by regenerating the HCRT sleep circuit

Generating human basal forebrain cholinergic neurons for treatment of dementia

Neurodegenerative disorders such as Alzheimer’s Disease, Parkinson’s Disease and Lewy body disease are associated with the loss of basal forebrain cholinergic neurons, which can lead to memory loss and dementia. In this project, we develop protocols for generating cultures of human basal forebrain cholinergic neurons from stem cells and through animal models, we assess the potential of these cells to be used as a transplantation cell therapy for treatment of cognitive deficits. This project is part of the EU H2020 consortium NSC-Reconstruct.

Studying neuroinflammation in in vitro stem cell models of Parkinson’s Disease

Recent studies in the field of Parkinson’s Disease has put increased focus on the role of neuroinflammation in the pathogenesis of the disease. In this project, we study the factors involved in neuroinflammation in Parkinson’s Disease through the use of complex in vitro models containing human neurons, astrocytes and microglia. This work is funded as a Michael J Fox Foundation/ASAP Research consortium

STEM-PD: developing a stem cell therapy for treatment of Parkinson’s Disease

In our lab at Lund University, together with the lab of Malin Parmar, we work in a long-standing collaboration to develop a cell therapy for treatment of Parkinson’s Disease. In this project, we produce human dopaminergic progenitor cells from human embryonic stem cells for transplantation therapy to replace the dopamine neurons which are lost in the brains of Parkinson’s Disease patients. This work has resulted in the development of a clinical stem cell product (STEM-PD), which is anticipated to go into clinical trial in Parkinson’s Disease patients in late 2021/early 2022.  

Funding

The projects above have received funding from the following sources:

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Lab members

Name Title Job responsibilities Image
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Alison Salvador Master-Student Kirkeby Lab Billede af Alison Salvador
Alrik Schörling Guest Researcher Kirkeby Lab Billede af Alrik Schörling
Amalie Holm Research Assistant Kirkeby Lab Billede af Amalie Holm
Andrea Asenjo Martinez Postdoc PhD student Billede af Andrea Asenjo Martinez
Anika Müller Research Assistant Kirkeby Lab Billede af Anika Müller
Arun Thiruvalluvan Postdoc Kirkeby Lab Billede af Arun Thiruvalluvan
Brenda Finlay Master-Student Kirkeby Lab Billede af Brenda Finlay
David Nørgaard Essenbæk Bachelor student Kirkeby Lab Billede af David Nørgaard Essenbæk
Ida Sophie Brun Master-Student Kirkeby Lab Billede af Ida Sophie Brun
Jens Bager Christensen Master-Student Kirkeby Lab Billede af Jens Bager Christensen
Matias Heide Ankjær Master-Student Kirkeby Lab Billede af Matias Heide Ankjær
Patrick Anders Aldrin Kirk Postdoc Kirkeby Lab Billede af Patrick Anders Aldrin Kirk
Sara Olivia Baungaard Master-Student Kirkeby Lab Billede af Sara Olivia Baungaard
Sarah Kieler Saietz Master-Student Kirkeby Lab Billede af Sarah Kieler Saietz
Ugne Dubonyte PhD Fellow Kirkeby Lab Billede af Ugne Dubonyte
Yu Zhang Guest Researcher Kirkeby Lab Billede af Yu Zhang
Yuan Li Guest Researcher Kirkeby Lab Billede af Yuan Li
Zehra Caldwell Abay-Nørgaard PhD Student Kirkeby Lab Billede af Zehra Caldwell Abay-Nørgaard