Understanding unique regulative machineries in HSCs towards ex vivo expansion of HSC and RBC
Value of Research
The health issues related to serious blood disorders like leukemia and genetic diseases remain a considerable burden to the EU countries. The development of blood and marrow transplantation (BMT) has been paramount in the development of effective treatments for various leukemia and genetic disorders of the blood system. However, there is still considerable mortality and morbidity related to BMT as a treatment modality, both in terms of engraftment failure and graft versus host disease. In addition, many patients cannot currently be treated because no suitable donor can be found or in terms of acute leukemia, the donor is identified too late. Cord blood samples contain hematopoietic stem cell (HSC) as well, which routinely are sufficient in number for pediatric patients, but inadequate for adult patients that may require up to 10 times more HSC than young children. Successful effective expansion of HSC will therefore generate many new donors for adult patients.
Despite recent advances in HSC research, it is still problematic to expand HSCs effectively in vitro. The reason can be summarized in two points; (1) the microenvironment called the hematopoietic stem cell “niche” seems to work towards maintenance of HSCs by inducing a dormant state where HSCs have less risk of mutational burden and physical stress (2) HSCs are rarely actively dividing in the body under physiological conditions. Although recent studies have suggested the existence of active HSCs, biology of these cells have poorly been understood compared to dormant HSCs.
Embryonic stem (ES) and induced pluripotent stem (iPS) cells are capable of unlimited proliferation without differentiation in cell culture. They divide symmetrically and maintain an immature phenotype in the presence of defined factors (LIF, bFGF) independent from any niche but retain differentiation abilities. Not only ES/iPS cells, but also some tissue-specific stem cells, e.g. neural stem cells (NSCs), are known to possess a strong, niche-independent, self-renewal capacity. In contrast to these cells, HSCs easily reduce their reconstitution potential, particularly in vitro. These facts have prompted us to ask the basic question if HSCs need additional factors to be amplified.
We therefore investigate regulations of dividing stem cells to understand what factors are missing and thereby necessary in HSCs, in order to achieve effective ex vivo HSC expansion.
Recent our findings strongly suggest involvement of protein quality control, including endoplasmic reticulum (ER) stress response, and metabolic control in HSC regulations.
- Identifying novel regulators that can expand HSCs ex vivo
- Discovering critical signaling pathways and metabolic regulations in HSCs, particularly in the actively dividing HSC population
- Understanding what determine stemness