The aim of the SFO Stem cells and Regenerative medicine is to support research and infrastructure within the field of stem cells and regenerative medicine. The SFO supports researchers, research programs and infrastructure at the Karolinska Institutet (KI) with or without collaboration with the health care system based on scope, quality, and the potential to strengthen and develop the field.
The steering committee for SFO stem cells and regenerative medicine has decided to award 12 grants for 2023 and potentially for 2024, depending on funding availability.
Each grant is 2 MSEK per year.
Sten Eirik Jacobsen
Harnessing the power of T cell immunity to unravel the stem cell dependency of sustained normal and malignant hematopoiesis
No studies have addressed the dependency of normal steady-state adult hematopoiesis or hematological malignancies on stem cells, following efficient and selective elimination of the stem cells in vivo. We aim to resolve this issue in mouse models of normal and malignant hematopoiesis through engineering of T cell receptors (TCRs) efficiently and specifically targeting hematopoietic stem cells. While there are no means to address this optimally in humans, the findings in mouse models will have important implications for the human cancer stem cell hypothesis and therapies.
Targeting glioblastoma stem-like cells using engineered lipid nanoparticles
Glioblastoma is thought to arise due to transformation of residual stem cells (hierarchical model) or dedifferentiation of post-mitotic glia (stochastic model); either way, stem-like cells drive the development of tumors. However, despite decades of efforts to develop targeted therapies, overall survival has remained poor. We will develop DNA lipid nanoparticle vectors targeting diverse glioblastoma stem cell states. Lipid nanoparticles are promising for their flexibility of design, simple manufacturing and ability to target different cell types, exemplified by the successful development of mRNA-LNP Covid-19 vaccines.
Less work has focused on LNP formulations with DNA payload, which provide an opportunity for longer-term modulation of cellular function compared to mRNA-based LNPs, and for programmability based on regulatory DNA elements.
More research is performed in Sten Linnarsson group.
Establishment of regenerative cell statesin multiple sclerosis: identifications of key transcription factors for oligodendrogenesis
Multiple sclerosis (MS) is characterized by an auto-immune attack on oligodendrocyte (OL)-derived myelin. Spontaneous remyelination driven by oligodendrocyte precursor (OPCs) and mature OLs has been described in MS, but eventually fails. We will determine how different OL-lineage cell states are established and identify transcription factors underlying their establishment.
We will perform pool CRISPR-based screenings, combining with single-cell and spatial omics, and assess the effect of these transcription factors on the differentiation/myelination potential of human OLs. This project will unveil new strategies to drive OL lineage to remyelinating states, which might lead to regenerative medicine approaches for MS.
More research is performed in Gonçalo Castelo-Branco group.
Vascular regeneration and functional implications from somatic mutations in age-associated vascular disease
We and others have analyzed somatic mutations in human tissues and showed that somatic cells accumulate thousands of mutations during development and aging.
While most of the mutations are likely harmless, some either contribute to disease and aging or are directly disease-causative, as in the formation of tumors in cancer. In this study, we will develop models to study clonal expansion of somatic mutations in the arterial wall during aging and disease.
More research is performed in Maria Eriksson group.
Cell regeneration in the adult human kidney in health and disease
Chronic kidney disease is estimated to affect more than 10% of the population. With no curative treatments to restore kidney function, clinical efforts have instead focused on slowing the progressive decline into renal failure. The potential for stimulating the regeneration of podocytes – the key cells of the glomerular filtration barrier whose loss is directly correlated with a decline in function – is of immense clinical interest.
We will use carbon-14 dating of nuclear DNA to determine the regenerative capacity of podocytes in the adult human kidney and assess whether stimulating endogenous podocyte cell replacement is a viable therapeutic option for kidney disease.
More research is performed in Kirsty Spalding group.
Exploring the regenerating enteric nervous system for applications in restorative therapy of gastrointestinal disease
Neuropathy within the enteric nervous system (ENS) contribute to congenital, degenerative and inflammatory gut disorders that lack satisfactory treatment. Following injury or inflammation, regeneration of both enteric neurons and glia have been observed, yet without that functional deficits are restored.
To achieve functional recovery, a balanced neuronal constitution would need to be re-created. We have recently determined general principles of embryonic diversification of enteric neuron subtypes, but the neuron identities emerging during adult neurogenesis remains unknown. In this project we aim to explore the potential and constraints of the regenerating ENS to pave the way for new regenerative strategies for treating neural deficits in the gut.
More research is performed in Ulrika Marklund group.
Epigenetic mechanism of the first human embryonic lineage choices
The first lineage choice made in human embryo development separates trophectoderm (TE) from the inner cell mass (ICM), separating extra- and embryonic cell fates. Upon implantation, TE gives rise to placental tissues while the ICM progresses via the epiblast stage to form the fetus. Together with Fredik Lanner’s group, we have been studying how epiplast identity is specified and maintained in a human embryonic stem cell model.
In the project, we will identify and study so-called epigenetic factors that guide cell fate decisions or provide barriers between different lineages in early human development, together orchestrating the ordered development of embryo and extraembryonic support tissues.
More research is performed in Simon Elsässer group.
Regionalization of esophageal progenitor cell fate and tumor potential
In many stem cell niches, stem and progenitor cells are tucked away in anatomically distinct locations, enabling exclusive interactions with niche signals that maintain stemness and prevent differentiation. In structurally simple epithelia such as the esophagus, no local stem cell niches have yet been identified.
Our work suggest that symmetrically fated progenitor cells are enriched in specific epithelial regions, indicating that local signal environments, or niches, impact progenitor fate and subsequently susceptibility to transformation. Here, we propose to characterize how progenitor cell location impacts esophageal homeostasis and tumor initiation.
More research in performed in Maria Genander group.
Development of an in vivo gene editing technology of hematopoietic stem cells to treat X-linked agammaglobulinemia
This project aims to use gene-editing of hematopoietic stem cells (HSCs) to treat an inherited immunodeficiency, X-linked agammaglobulinemia (XLA), at Karolinska University Hospital. XLA patients carry a mutated BTK gene, thereby, lacking a functional BTK. Together with researchers at UCLA and close collaborators at KI, HSCs from XLA patients will be gene-edited by homology-directed, so-called CRISPR methods.
Hopefully, this preclinical attempt will restore the expression of normal BTK protein, which is non-functional in XLA patients, and pave the way for a clinical trial. In parallel, the project aims to increase the editing efficiency of HSCs by developing a novel delivery system of Cas9-RNPs (components of CRISPR) to enhance editing efficiency.
More research is performed in Joel Nordin group.
Molecular pathogenesis of germline cancer predisposition in hematopoietic stem cells
Myeloid malignancies are clonal disorders of hematopoietic stem cells. We aim to better understand how certain genetic mutations in these cells predispose and lead to development of myeloid neoplasms, such as MDS and AML. In this project, we use patient-derived induced pluripotent stem cells (iPSC) from germline carriers of disease-prone variants. These personalized cell lines provide a unique opportunity to model and study the continuum of myeloid disease in vitro, as iPSCs can be readily differentiated into blood cells but also allow for genetic engineering, functional readouts, and validation of new drug targets.
Leveraging state-of-the-art multiomics, we will obtain mechanistic insights into the pathogenesis of hematopoietic stem and progenitor cells (HSPCs) to ultimately identify strategies towards blocking malignant transformation and restoring hematopoietic output in myeloid malignancies.
More research is performed in Vanessa Lundin group.
Towards the first hospital-based treatment platform for sickle cell anemia using gene editing of autologuous blood stem cells
Sickle cell disease (SCD) represents a huge burden to the healthcare system worldwide as curative alternatives are limited to allogeneic stem cell transplantation (SCT). Here, the lack of HLA-matched donors and associated potentially life-threatening alloreactive risks have deprived several patients from this curative option. Recent opportunities with gene editing have raised hope to cure this growing patient group in need. In particular, induction of fetal hemoglobin has been proven to be efficient for treating SCD.
Today, no patient in Sweden has access to gene therapy and sky-rocketing costs make industry-driven manufacturing unlikely in a foreseeable future. We are planning the development of Sweden’s first hospital-based gene editing platform using CRISPR-Cas9 and Base Editing methodologies with the goal to treat the first patient within the three years with gene-edited CD34+ selected autologous SCT.
More research is performed in Stephan Mielke group.
Systemic mastocytosis: deciphering the cellular origin of disease and establishing CCL23 as a diagnostic and prognostic biomarker
Most systemic mastocytosis (SM) patients carry the driver KIT D816V mutation. The majority will have a normal life expectancy however around 10% have a malignant disease with short overall survival. The cellular origin of disease, and what factors determine the clinical fate, are unknown. In addition, there is a lack of disease biomarkers.
We will establish CCL23 as diagnostic and prognostic disease biomarker and test our hypothesis that the cell of origin of the KIT D816V mutation (stem cell or progenitor) determines the clinical disease course.
Our studies will unravel the cellular origin of SM, establish a new biomarker enabling earlier treatment initiation, improving patient quality of life.
More research is performed in Johanna Ungerstedt group.