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 SFO has during 2021 decided to support four (4) senior research grants, six (6) junior research grants and two (2) clinical research grants for projects within the field of stem cells and regenerative medicine.
Each project will be supported with a total of 4 MSEK for 2 years.
Building relay circuits from resident neural stem cells
The injured spinal cord has the capacity to spontaneously build relay circuits from spared tissue after partial injuries. Relay circuit formation is however limited by the availability of spared neurons and axons at the injury site, as resident neural stem cells in the adult spinal cord generate only glia after injury.
We will carry out a single-cell CRISPR-activation analysis using therapeutically relevant gene-delivery vectors to identify factors that elicit neurogenesis by local neural stem cells in vivo after spinal cord injury, aiming to enable the formation of regenerative relay circuits from within.
More research is performed in Jonas Frisén group.
Elucidating the regenerative potential of astrocyte-derived striatal neurogenesis
The adult mammalian brain has a poor regenerative capacity and neuronal replacement is extremely limited. Astrocytes have emerged as a potential source for new neurons. However, it has been unclear if astrocyte-derived neurons become functional, which neuronal properties they possess and if they can integrate into the adult circuitry.
In this project, we will induce striatal neurogenesis by astrocytes and study the intrinsic electrophysiological properties of adult-born neurons and their synaptic interconnectivity within the striatal microcircuitry. Furthermore, we will test whether induced striatal neurogenesis from local astrocytes could be of therapeutic value for the treatment of Parkinson disease.
More research is performed in Christian Göritz group.
Decoding molecular and cellular mechanisms controlling self-renewal and regeneration of skin
Skin has become one of the best-studied organs for investigating tissue stem cell biology. However, the molecular and cellular triggers governing stem cell differentiation and hair follicle induction in adult skin are largely unknown, which hampers the advancement towards tailor-made skin therapies. With this research program we will determine the boundary to stem cell plasticity and reversibility, with the long-term aim to re-activate skin stem cells in a controlled manner.
Specifically, we will investigate whether tissue-resident immune cells regulate epidermal turnover and if uneven organelle inheritance influences stem-cell fate decisions. In addition, through precise molecular signal activation we will work towards a viable strategy for inducing de novo hair follicles in human skin, which is of worldwide importance for patients with skin replacement needs.
More research is performed in Maria Kasper group.
Development of ultra-pure progenitors using plurifaceted single-cell proteomics
Cell heterogeneity in progenitor population intended for transplantation is undesired as the presence of off-target cells can lead to poorly controlled clinical outcomes. In this project we will reduce the cell-to-cell variability by synchronizing the beginning of cell differentiation with our novel RNAi-based method. For precise monitoring this variability we will employ our plurifaceted bulk proteomic analysis as well as develop a novel plurifaceted single-cell proteomics approach.
Using these new analytical techniques we will produce a comprehensive plurifaceted proteomic atlas of human neuronal lineage as a novel resource for regenerative medicine, with relevance to Parkinson’s disease treatment.
More research is perfomed in Roman Zubarev group.
Deciphering the function of SAMD9 and SAMD9L tumor suppressors in stemcell disorders
Variants in the genes encoding SAMD9 and SAMD9L are associated with severe developmental disorders as well as hematopoietic stem cell defects that can cause hematological malignancies. They are potent tumor suppressors, but how these homologous, evolutionary conserved proteins arrest cell proliferation remains unknown. Our project aims to mechanistically decipher how SAMD9 and SAMD9L regulate protein translation using a range of cutting-edge methods. We will also probe how wild-type SAMD9 and SAMD9L are activated and explore paths to exploit their potent anti-proliferative activity for the development of novel cancer therapeutics. Insights will provide fundamental knowledge of how these interferon-stimulated genes profoundly regulate stem cells and potentially can be exploited in cancer therapy.
More research is performed in Yenan Bryceson group.
Regenerating human ovaries in vitro
Ovaries contain the reserve of immature oocytes enclosed in follicles and are indispensable for fertility in women. Oocytes are the limiting factor in human reproduction; while fertile men produce millions of sperms daily, fertile women make only one mature oocyte a month. Diverse approaches ranging from in vitro production of oocytes to artificial ovaries are being developed to provide new fertility treatment options, but the progress is slow and hampered by our shallow knowledge of human ovarian biology.
We have recently mapped the single-cell composition of the fertile human ovarian cortex. Here, we will use this blueprint to regenerate fertile ovarian cell niche in vitro for the growth and maturation of follicles.
More research is performed in Pauliina Damdimopoulou group.
Revealing deleterious gene dosage effects on germline specification and testicular stem cell niche in Klinefelter syndrome by single-cell technology
Klinefelter syndrome (KS) is estimated to occur as frequent as 1/600 births and caused by the presence of at least one additional X-chromosome resulting in non-obstructive azoospermia. KS is often marked by few distinguishing features before puberty for early diagnosis. However, the onset of puberty leads to accelerated degeneration of the testicular environment and greatly reduced potential of fertility preservation. Our lab is interested in the developmental principles of the germline in health and disease. We will use KS patient-derived iPSCs for differentiation towards germ cells to investigate supernumerary X chromosomes activity and global gene dosage effects on pluripotency, germ cell specification, clonal propagation.
Together with in vitro modeling and single-cell profiling, we aim to understand the molecular mechanisms underlying mutual influence of germ cells and niche compartment in relation to global transcriptional regulatory network.
More research in performed in Qiaolin Deng group.
How is human growth maintained throughout childhood?
Long-bone growth during childhood allows us to reach our adult height. Children's long-bones must be able to withstand the rigorous loading associated with childhood, whilst simultaneously growing. This dilemma is solved by narrow cartilage organs present near the ends of all growing long-bones, which are called growth plates.
Within each growth plate, an ongoing supply of cartilage cells (chondrocytes) is needed for the bone to grow. In this project, we aim to understand how growth plates continuously produce the chondrocytes needed for humans to reach our final height.
More research is performed in Phillip Newton group.
Modes and mechanisms of dosage compensation upon chromosome copy number imbalance
Correct gene expression dosage is vital for normal cell function. Chromosomal copy number variation (CNV) results in imbalance of hundreds of genes in one sweep and is not well tolerated by the cell. Indeed, most aneuploidies arising in the germline result in embryo termination, and CNVs are common alterations in cancer cells. The X chromosome is a remarkable exception in this context, as female cells naturally carry two copies while male cells cope with one. Our research dissects mechanisms of dosage compensation, and how transcription is modulated to resolve gene-dose imbalance.
Furthermore, we explore autosomal dosage compensation upon aneuploidy and pinpoint genes and features underlying compensation and sensitivity. Understanding of transcriptional dosage changes upon CNVs is critical for future clinical use of embryonic and induced pluripotent stem cells.
More research is performed in Björn Reinius group.
Bone tissue engineering by stem cells and calcium phosphate nanobiomaterials
The overarching aim is to exploit the nanobiomaterial calcium phosphate for bone tissue engineering utilizing stem cells. Calcium phosphate has similar chemical structure to the inorganic components of bones. For this reason there has been interest in calcium phosphate biomaterials in bone tissue regeneration, especially upon their interaction with stem cells. Here, we will capitalize on our expertise and produce an arsenal of nanostructured calcium phosphate nanobiomaterials by flame aerosol synthesis and study their interactions with stem cells.
The systematic approach for investigation of interactions between stem cells and calcium phosphate nanobiomaterials will provide knowledge and insight into the fundamental principles and understanding to assist translation into clinics and further promote their use in regenerative medicine.
More reseach is performed in Georgios Sotiriou group.
Clinical grade human neural stem/progenitor cell therapy for chronic spinalcord injury
Chronic spinal cord injuries remain without any therapeutic intervention for repair. Human neural stem/progenitor cells (termed NESCs) derived from induced pluripotent stem cells could provide a regenerative therapy for cyst formation (syringomyelia) and dorsal column injuries together with peripheral nerve grafts. Transplantation of human NESCs effectively prevents further cyst expansion and also reduces cyst volumes significantly.
Axon regeneration after peripheral nerve graft (PNG) transplantation in a chronic spinal cord injury remains sparse. Here, we will investigate if NESCs transplantation in these two conditions can provide additional regeneration by providing a neuronal relay.
More research is performed in Mikael Svensson group.
Prediction of relapse after allogeneic stem cell transplantation by identifying patient- specific mutations in the hematopoietic stem and progenitor cell compartment in patients with myelodysplastic syndrome
We have developed and evaluated a method for tracing patient-specific mutations in patients in myelodysplastic syndrome (MDS). These can be used as markers for minimal residual disease (MRD) and used for relapse prediction after allogeneic stem cell transplantation. The Nordic MDS group is now planning for a prospective study using these markers to initiate pre-emptive treatment in MRD+ patients.
By analysing MRD on sorted stem and progenitor cells (CD34+ cells) from bone marrow and blood, we aim to further enhance sensitivity and to replace bone marrow with blood sampling.
More research is performed in Magnus Tobiasson group.