Olov Andersson

By bridging developmental biology, genetics and drug discovery through the use of the zebrafish model, we elucidate organogenesis and related mechanisms of disease. Our current focus is on small molecules and proteins that stimulate cellular processes to reverse diabetes and diabetes-associated diseases, including cancer and Alzheimer’s disease.

Most notably, regenerating functional insulin-producing beta-cells might prove a better treatment for diabetes, which is at present controlled but not cured by insulin injections. Diabetes is characterized by elevated blood glucose levels, a consequence of insufficient insulin supply and/or insulin resistance. Despite mechanistic differences, both type 1 and type 2 diabetes feature a reduction in functional beta-cells. Experimental ablation of beta-cells by chemical treatment or partial pancreatectomy in zebrafish and rodents is followed by significant recovery of the beta-cell mass, indicating that the pancreas has the capacity to regenerate. This regenerative capacity could potentially be exploited therapeutically - if the underlying mechanisms were better understood.

We perform unbiased screening of thousands of chemicals and genes in zebrafish to identify drug candidates, genes, secretory proteins, and cellular mechanisms that promote regeneration of beta-cells or formation of enteroendocrine cells, and ameliorate diabetes-associated diseases such as cancer and Alzheimer’s disease.

Left: At three days after fertilization, the zebrafish has already developed a pancreas (exocrine pancreas shown in green; endocrine pancreas shown in red), liver and gut tube (both shown in white). Right: Using zebrafish, small molecule screening can be conducted as in vivo drug discovery in 96-well format (one well fits 3 zebrafish larvae).

The zebrafish model is particularly advantageous for studying organogenesis due to the simplicity of its organ structures, which allows for rapid analyses of cellular changes. Deciphering the fundamental mechanisms of organogenesis can provide important insights into cell regeneration, e.g. via morphological observations using confocal microscopy, lineage-tracing, and mechanistic characterization through single-cell transcriptomics. Moreover, zebrafish embryos are amenable to efficient transgenesis, mutagenesis, and drug delivery.

By using a wide range of techniques, we are investigating several different cellular mechanisms and screening for disease-modifying drugs in the following areas.

1. Beta-cell regeneration in diabetes models:

  • Inducing beta-cell neogenesis
  • Promoting beta-cell proliferation
  • Stimulating beta-cell redifferentiation or maturation
  • Generating ectopic insulin-producing cells

2. Enteroendocrine cell formation for improved glucose control:

  • Stimulating differentiation of cells that produce incretins (GLP-1 & GIP)
  • Decoding differentiation into various secretory cells in the gut

3. Diabetes-associated diseases:

  • Unraveling metabolic influences and its possible treatment of cancer
  • Targeting neurodegenerative diseases such as Alzheimer’s disease

Mechanistic insights of drug action can be deduced from scRNA-seq analyses. Here exemplified by UMAP (left), pseudotime (middle) and PAGA (right) after treatment of beta-cells with Harmine (Harm), HG-9-91-01 (HG) or co-treatment with HG + Harm, showing that HG drives beta-cells through a transient state of unfolded protein response (purple, node 4) prior to cell cycle entry (red, node 3), along the red arrow.

In sum, we aim to identify and characterize chemicals, drug candidates, signaling pathways, and cellular mechanisms that can induce the regeneration of beta-cells or the formation of enteroendocrine cells, with the overarching goal of developing new therapies for diabetes and diabetes-associated diseases.

Examples of published articles:

Inducing beta-cell neogenesis:

  • Decoding pancreatic endocrine cell differentiation and beta-cell regeneration in zebrafish. Mi J, Liu KC, Andersson O. Science Advances. 2023 Aug 18;9(33):eadf5142.
  • MNK2 deficiency potentiates β-cell regeneration via translational regulation. Karampelias C, Watt K, Mattsson CL, Ruiz ÁF, Rezanejad H, Mi J, Liu X, Chu L, Locasale JW, Korbutt GS, Rovira M, Larsson O, Andersson O. Nature Chemical Biology. 2022 Sep;18(9):942-953.

Promoting beta-cell proliferation:

  • in vivo screen identifies a SIK inhibitor that induces β-cell proliferation through a transient UPR. Charbord J, Ren L, Sharma RB, Johansson A, Ågren R, Lianhe Chu L, Tworus D, Schulz N, Charbord P, Stewart AF, Wang P, Alonso LC, Andersson O. Nature Metabolism. 2021 May;3(5):682-700.

Stimulating beta-cell redifferentiation or maturation:

  • Adjudin improves beta-cell maturation, hepatic glucose uptake and glucose homeostasis. Ren L, Charbord J, Chu L, Kemas AM, Bertuzzi M, Mi J, Xing C, Lauschke VM, Andersson O. Diabetologia. 2024 Jan; 67(1), 137-155.

Generating ectopic insulin-producing cells:

  • Insulin-producing β-cells regenerate ectopically from a mesodermal origin under the perturbation of hemato-endothelial specification. Liu KC, Villasenor A, Bertuzzi M, Schmitner N, Radros N, Rautio L, Mattonet K, Matsuoka RL, Reischauer S, Stainier DY, Andersson O. Elife. 2021 Aug 17;10:e65758.

Stimulating differentiation of cells that produce incretins:

  • In vivo drug discovery for increasing incretin-expressing cells identifies DYRK inhibitors that reinforce the enteroendocrine system. Chu L, Terasaki M, Mattsson C, Teinturier R, Charbord J, Dirice E, Liu KC, Miskelly MG, Zhou Q, Wierup N, Kulkarni RN, Andersson O. Cell Chemical Biology. 2022 Sep 15;29(9):1368-1380.e5.

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