Hematopoietic stem cell expansion

PhD ceremony: Ms. M.A. Walasek, 12.45 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Hematopoietic stem cell expansion

Promotor(s): prof. G. de Haan

Faculty: Medical Sciences

Expansion of fully functional self-renewing, multi-potent and engraftable hematopoietic stem cells (HSCs) is expected to be highly beneficial for stem cell-based therapies and represents a long-standing goal of stem cell biology. Despite intensive studies, defining the in vitro culture conditions that can maintain HSC’s characteristic properties of self-renewal and lack of differentiation, has proven to be difficult. Therefore, there is much interest in understanding molecular and environmental determinants governing HSC fate decisions, as well as manipulation of HSC culture conditions to efficiently expand them ex vivo. The aim of the first part of this thesis was to identify new intrinsic regulators of hematopoiesis. The important role of non-coding RNAs, microRNAs, in regulating hematopoiesis is described. Though characterization of intrinsic mechanisms involved in HSCs regulation is crucial for our understanding of factors favoring self-renewal over differentiation, extrinsic stimulation of HSCs amplification might be a preferred tool in clinical expansion protocols. In the second part of this thesis, the potential of distinct small molecule compounds to manipulate HSC’s fate in vitro have been explored. One of the important findings in this study was that supplementing the HSC cultures with the combination of two small molecules, valproic acid and lithium, resulted in the preservation of stem cell phenotype and functionality. Findings that the fate of HSCs can be modulated chemically by the addition of small molecules to the culture media is promising in light of ex vivo HSC expansion and may lead to novel approaches in ex vivo HSC culturing systems.