Research | Frisén Lab

We explore how old cells are replaced during physiological conditions, and how cell replacement and lineage progression are affected by injuries like stroke, spinal cord injury or myocardial infarction, and by diseases like cancer or multiple sclerosis.

One driving goal of our lab is to help the body replace worn-out or damaged cells and tissues. To reach this goal, one approach is to recruit and boost the body's own mechanisms for cell replacement. To achieve this, it is important to identify cells with the capability to replace others, and to understand how they are controlled. To this end, we have a keen interest in developing methods to interrogate cell renewal and cell lineage relationships in humans.

Cell Generation and Lineage Tracing in Mice and Humans

Adult human neurogenesis

We study adult human neurogenesis, the generation of new neurons in the adult brain, focusing on the dentate gyrus of the hippocampus and the striatum. We integrate single-nucleus RNA sequencing with spatial biology techniques (RNAscope, Visium HD, Xenium), which allows us to profile the gene expression of individual nuclei and anchor these profiles within tissue architecture to reveal the distribution of neural progenitors and immature neurons.

To detect very rare, dividing progenitors we enrich Ki67-positive nuclei by flow cytometry and then apply machine-learning classifiers (for example scPred and scANVI) together with RNA-velocity and pseudotime analyses to reconstruct differentiation trajectories. We also use a retrospective birth-dating strategy developed in our lab that exploits incorporation of nuclear-bomb-test-derived ¹&sup4;C into genomic DNA during cell division; by measuring ¹&sup4;C we quantify cell turnover across the human lifespan.

Using these complementary molecular, spatial and computational tools, we investigate turnover of neurons, oligodendrocytes and microglia in healthy brains and in brains from patients with stroke, multiple sclerosis, Alzheimer's disease, Parkinson's disease and depression.

Researchers: Marta Paterlini, Ionut Dumitru

Spatiotemporal mapping of human hippocampal neurogenesis and disease risk

The hippocampus is essential for episodic memory formation, spatial learning, regulating mood, and stress responses. It plays a key role in encoding and consolidating information and is one of the few regions of the human brain where neurogenesis persists into adulthood. Although snRNA-seq studies have made progress in characterizing its cellular diversity, the spatial landscape and its tissue niches remain relatively poorly defined.

Our goal is to study when, where, and how regulatory pathway activity and complex trait risk genes influence the hippocampus during neurogenesis. We utilize biostatistical methods, spatially resolved transcriptomics, and snRNA-seq datasets, and integrate these with gene sets for homeostatic regulatory pathways and complex traits. Using these approaches, we investigate spatial niches, developmental trajectories, and intercellular communication dynamics to elucidate the spatiotemporal organization of the granule cell lineage in the dentate gyrus during neurogenesis.

Researcher: Linda Kvastad

Spatial lineage tracing in human tissues

Reconstructing cell lineage relationships across human tissues requires approaches that capture both genomic identity and spatial context. By analyzing genomic variation — including somatic mutations and structural variants — we characterize the clonal architecture of cells within their native tissue environment.

Earlier work examined the spatial clonality and evolution of T and B cells in lymphoid tissues and breast cancer. Ongoing efforts extend lineage reconstruction to broader cell types and incorporate the development of new computational and experimental methods for variant detection and spatial analysis.

Researcher: Qirong Lin

Cancer, Immunology and Cancer Immunology

Clonal dynamics of the hematopoietic system

We are interested in the clonal dynamics of biological systems. We have investigated this primarily in the context of healthy human T cell populations because these cells can be tracked easily on the basis of their shared T cell receptors. In the future, we aim to extend these studies to other hematopoietic lineages in healthy and disease states and other organ systems.

The long-term goal of these studies is to better understand how complex tissues are built and maintained at the level of individual cells and their progeny. This research could have implications for regenerative medicine as well as for determining how ageing and injuries lead to malignancies in different tissues.