Group of Brain Development and Disease

Using STEM CELLs to model the Brain’s Role in Aging and Involvement in  Neurodegeneration

Research group’s focus:

To determine novel mechanisms involved in neurodevelopment, aging and neurodegenerative diseases.  We use human and porcine pluripotent and neural stem cells, as well as embryonic pig brains to model human brain development and to investigate late-onset diseases, such as Alzheimer’s disease. We also use the embryonic pig brain as a tool for improving in-vitro differentiation protocols of pluripotent stem cells into varying brain cell types.

Uncovering the cellular diversity of the developing brain provides extraordinary insight into the complexity of this organ and not only gives us new evidence for the function and origins of brain diseases but also a total fascination for the mind and its matter.

Current projects

Stellate cell project 

We are particularly interested in the role of the entorhinal cortex in Alzheimer’s disease and why it is one of the first regions of the brain that is affected by the disease. In this project, we have performed detailed investigation of the anatomical and molecular make-up of the entorhinal cortex using the developing pig brain and are using state-of-the-art single-cell RNA sequencing technology to discover more details on the stellate cell located in the entorhinal cortex and its role in the disease. The aim is to produce a stellate cell in the dish from human induced pluripotent stem cells and study why it is particularly susceptible in Alzheimer’s disease.  

Funded by Innovation Foundation (Brainstem) and The Danish Council for Independent Research: Technology and Production

Main finding

This review highlights the progress that pluripotent stem cells have made in being able to remodel complex tissue types such as the blood-brain barrier.
Paving the way towards complex blood-brain barrier models using pluripotent stem cells.

This study was the first to produce an in-vitro pig cell model of Alzheimer’s disease. Neural progenitors were studied for early phenotype of the disease and several mechanisms related to AD pathology could be seen.
Embryonic stem cell-derived radial glial cells from the APPsw transgenic pig show altered APP activity and tau splicing as well as perturbations in the cell cycle.

It is challenging to produce bona-fide iPSCs in the pig. In this study, we found a subpopulation of cells in pig fibroblasts that are reprogrammable, whilst other fibroblasts are not, suggesting that reprogramming success is critically dependent on the characteristics of the original cells.
Identification of SSEA-1 expressing enhanced reprogramming (SEER) cells in porcine embryonic fibroblasts.

Research funding

            

Publications

  1. Lauschke, K., Frederiksen, L., and Hall, V.J. (2017). Paving the way towards complex blood-brain barrier models using pluripotent stem cells. Stem cells and Development. 26(12):857-874.
  2. Li, D., Secher, J.O., Juhl, M., Mashayekhi, K., Nielsen, T.T., Holst, B., Hyttel, P., Freude, K.K. and Hall, V.J. (2017) Identification of SSEA-1 expressing enhanced reprogramming (SEER) cells in porcine embryonic fibroblasts. Cell Cycle. 16(11):1070-1084.
  3. Tubsuwan, A., Pires, C., Rasmussen, M.A., Schmid, B., Nielsen, J.E., Hjermind, L.E., Hall, V., Nielsen, T.T., Waldemar, G., Hyttel, P. et al (2016) Generation of induced pluripotent stem cells (iPSCs) from an Alzheimer’s disease patient carrying a L150P mutation in PSEN-1. Stem cell research. 16(1): 110-112.
  4. Hall, V.J., Lindblad, M.M., Jakobsen, J.E., Gunnarsson, A., Schmidt, M., Rasmussen, M.A., Volke, D., Zuchner, T., Hyttel, P. (2015) Embryonic stem cell-derived radial glial cells from the APPsw transgenic pig show altered APP activity and tau splicing as well as perturbations in the cell cycle. Disease Models and Mechanisms 8(10):1265-78. 
  5. Freude, K., Pires, C., Hyttel, P. and Hall, V.J. (2014) Induced pluripotent stem cells derived from Alzheimer’s disease patients: the promise, the hope and the path ahead. Journal of Clinical Medicine. 3(4):1402-36.
  6. Hall, V.J. and Hyttel, P. (2014) Breaking down pluripotency in the porcine embryo reveals both a premature and reticent stem cell state in the inner cell mass and unique expression profiles of the naïve and primed stem cell states. Stem Cells and Development. 23(17):2030-45.
  7. Hall, V.J., Kristensen, M., Rasmussen, M.A., Ujhelly, O., Dinnyes, A., Hyttel, P. (2012). Temporal repression of endogenous pluripotency genes during reprogramming of porcine induced pluripotent stem cells. Cellular Reprogramming. 14(3):204-216.
  8. Yu, G., Jammes, H., Rasmussen, MA., Oestrup, O., Beaujean, N., Hall, VJ., Hyttel, P. (2011) Epigenetic regulation of gene expression in porcine epiblast, hypoblast and trophectoderm and epiblast derived neural progenitor cells. Epigenetics. 6(9):1149-1161.
  9. Rasmussen, M.A., Hall, V.J., Carter, T.F., Hyttel, P. (2011). Directed differentiation of porcine epiblast-derived neural progenitor cells into neurons and glia. Stem Cell Research 7(2):124-136.
  10. Yu, G., Hyttel, P, and Hall, V.J. (2011). Dynamic changes in epigenetic marks and gene expression during porcine epiblast specification. Cellular Reprogramming. 13(4):345-360.