Stem Cell Regulators - Main Research Topic

Hematopoiesis is maintained by a small number of hematopoietic stem cells (HSCs) that can self-renew and differentiate into all hematopoietic lineages. HSCs have been used therapeutically in the clinic for several decades in life-saving treatment of malignant diseases and hematological disorders through continuously improved bone marrow (BM) transplantation protocols. Insufficient stem cell numbers is, however, a significant constraint in many settings of both autologous and allogeneic BM transplantation. Expansion of HSCs outside the body has, therefore, for many years been one of the most desired, yet elusive goals in experimental hematology and transplantation medicine.

The main objectives of our research are:

1. To systematically, in a high throughput fashion, identify and characterize regulators of self-renewal in murine HSCs
2. To define strategies for stem cell expansion applicable in settings of clinical bone marrow transplantation and gene therapy.

We have developed a genetic screening methodology in HSCs based on RNA interference (RNAi) and large short hairpin RNA (shRNA) retroviral vector libraries. Large numbers of HSCs from mice are transduced with the shRNA libraries and we screen these cells in a pooled fashion for enhanced self-renewal using positive selection assays for HSC activity in vitro and in vivo. To date, several genes with known functions in growth control and tumor suppression, in addition to unknown genes, have been retrieved in independent screens and functionally validated

Candidate genes identified from the screening experiments are characterized in detail for their role in regulation of HSCs in vitro and in vivo and tested using strategies for stem cell expansion.

We hope that these studies will reveal new gene targest for HSC expansion and thus lead to significant improvements of current bone marrow transplantation therapies.