Section of Pharmacogenetics: Herland-lab

Our research is focused on the neurovascular unit and surrounding parenchymal neural tissue.

Group members

Anna Herland PhD, Assistant professor, Group Leader
Polyxeni Nikolakopoulou Postdoc
Anders Lundin PhD student, primary affiliation Anna Falk lab

Background

Our research is focused on the neurovascular unit and surrounding parenchymal neural tissue.

We use human primary cells and stem cell-derived cells to form in vitro models with controlled cellular microenvironment. These systems are used to study the impact of cellular interactions that control the function of the neurovascular unit.

We have shown that the cellular microenvironment of human stem-cell derived forebrain cholinergic neurons can sensitize the cells to disease-like neurodegenerative stimuli (Zhang et al. Biomaterials 2014). In a three-dimensional gel culture system, but not in traditional cultures, the cells could display a response in the mechanotransduction hub-molecule p21 activated kinase similar to what has been seen Alzheimer’s patients.

We are using micro-engineered Organ Chip models to create neurovascular models, where we can re-create physiological interactions in-between the vascular, perivascular and parenchymal brain tissue. We have demonstrated how the microenvironment of a three-dimensional Blood-Brain-Barrier Organ Chip model improved the barrier function and displayed a more in vivo like neuro-inflammatory response compared to traditional models (Herland et al. PLoS One 2016). Another Organ Chip method allowed us to discriminate barrier alternating effects and impact on electrophysiology (Maoz, Herland et al. Lab on Chip 2017).

The Herland lab has a dual affiliation with the Department of Micro and Nanosystems at the Royal Institute of Technology (KTH)

KTH is the main location for development of the Organ Chip devices and integrated sensor technology.

Projects

  1. Metabolic interactions and transport event across the neurovascular unit

The neurovascular unit is a gate-keeper of the central nervous system.

We use stem cell-derived Organ Chip models to re-create the human blood barrier function, both in terms of passive permeability and relevant transporter functionality.

This model serves to predict blood-brain-barrier passage of novel drugs and known toxicants and the possible drug-drug interactions effecting transport event. Moreover, we are also using micro-engineering to build up a holistic model of the neurovascular unit also integrating interactions with models of neuronal tissue. Specifically, we use this model as a tool to study the metabolic interplay in-between the constituting cells by evaluating transcriptomic and proteomic profiles in combination with targeted and untargeted mass spectroscopy to study metabolic signatures.

The Organ Chip models allows for integration of all from vascular endothelial cells to functional neuronal cells, not possible in static cultures while giving a temporal and spatial resolution not doable in vivo. We aim to study the metabolic changes of the neurovascular unit under steady state and under stimuli of neuropsychiatric drugs, known to have metabolic side effects.

  1. Functional in vitro Models of Human Neuronal and Astrocyte interactions

For the human central nervous system, it is very difficult to pursue studies of disease mechanisms, development of drugs and predict drug side effects. One reason is that there are no in vitro (outside body) methods that are truly physiologically relevant.

This project aims at developing such models in the form of functional cell cultures of neurons and astrocytes. To have a renewable and reproducible cell source we will use human induced pluripotent stem cells, derived from skin samples of healthy controls or patients, and differentiate these to specific types of neurons or astrocytes. A key aspect of the project is to create an in vivo like interface between the two main cell types of the brain, a task we will tackle with co-cultures in two and three-dimensional (2D/3D) systems. We will develop 3D hydrogel culture systems optimized to neural cells. We will specifically study disease mechanisms in Alzheimer’s disease, but all methods will also be useful to predict drug side effects in neural cells. Focus will be on developing scalable methods that are easily applicable in industrial settings.

This project is run as an industrial PhD project with AstraZeneca in collaboration with Anna Falk lab at Karolinska Institutet.

  1. Human stem cell-derived microglia in models of neuro-inflammation

Microglia are the resident immune cells of the brain. Recently, a few reports have been published on how to derive microglia from pluripotent stem cells, via hematopoietic differentiation.

The aim of the project is to study human microglia biology, specifically the homing of microglia progenitors to the brain, their maturation process and routes of activation in neuro-inflammation. We will use our micro-engineered neurovascular models combined with stem cell-derived progenitors of microglia to study these processes.  This allows us to systematically study processes of transendothelial migration and cellular interactions in-between the neurovascular cells and microglia.

Financial support

  • Vetenskapsrådet
  • Knut och Alice Wallenbergs stiftelse
  • AstraZenca
  • Alzheimersfonden
  • Forska utan djurförsök

Publications

Organs-on-Chips with combined multi-electrode array and transepithelial electrical resistance measurement capabilities.
Maoz B, Herland A, Henry O, Leineweber W, Yadid M, Doyle J, et al
Lab Chip 2017 Jun;17(13):2294-2302

Distinct Contributions of Astrocytes and Pericytes to Neuroinflammation Identified in a 3D Human Blood-Brain Barrier on a Chip.
Herland A, van der Meer A, FitzGerald E, Park T, Sleeboom J, Ingber D
PLoS ONE 2016 ;11(3):e0150360

Phenology of deer ked (Lipoptena cervi) host-seeking flight activity and its relationship with prevailing autumn weather.
Mysterud A, Madslien K, Herland A, Viljugrein H, Ytrehus B
Parasit Vectors 2016 Feb;9():95

Engineered in vitro disease models.
Benam K, Dauth S, Hassell B, Herland A, Jain A, Jang K, et al
Annu Rev Pathol 2015 ;10():195-262

Full list of publications can be found at https://www.ncbi.nlm.nih.gov/pubmed/?term=herland+a

Contact

Senior researcher

Anna Herland

Organizational unit: Ingelman-Sundberg Magnus group - Pharmacogenetics
E-mail: Anna.Herland@ki.se