Ex Vivo Expansion of Hematopoietic Stem Cells for Therapeutic Purposes: Lessons from Development and the Niche

Abstract

Expansion of hematopoietic stem cells (HSCs) for therapeutic purposes has been a “holy grail” in the field for many years. Ex vivo expansion of HSCs can help to overcome material shortage for transplantation purposes and genetic modification protocols. In this review, we summarize improved understanding in blood development, the effect of niche and conservative signaling pathways on HSCs in mice and humans, and also advances in ex vivo culturing protocols of human HSCs with cytokines or small molecule compounds. Different expansion protocols have been tested in clinical trials. However, an optimal condition for ex vivo expansion of human HSCs still has not been found yet. Translating and implementing new findings from basic research (for instance by using genetic modification of human HSCs) into clinical protocols is crucial to improve ex vivo expansion and eventually boost stem cell gene therapy.

Cell Signaling Pathway Reporters in Adult Hematopoietic Stem Cells

“…Although several attempts haven been completed to mimic the HSC niche in for example (3D) scaffolds or in bioreactors, researchers have not reached the point of re-enacting the cues required in HSC regulation. Before coming to that accomplishment, more knowledge should be gained on how HSCs respond to HSC niche ligands under physiological and transplantation settings in vivo [ 87 ]. In particular for human HSC lympho-myeloid engraftment, humanized immune-deficient xenograft models could provide insight into the discrepancies between human and murine signaling pathway function to clarify translation into clinical application [ 88 ].…”

Crosstalk Between the Hepatic and Hematopoietic Systems During Embryonic Development

“…Another possibility to obtain higher numbers of HSCs would be to expand them ex vivo prior to transplantation. Distinct cytokine/growth factor cocktails have shown promising for expansion of HSCs, yet, limited success was reported in clinical studies due to a lack of LT-HSC expansion and rather proliferation of downstream progenitors together with undesirable stem cell differentiation – reviewed in Kumar and Geiger (2017) and Tajer et al (2019) . Cytokines currently used for ex vivo HSC expansion include KITL, TPO, IL-3, and FLT3L.…”

Mesenchymal stromal cell‐derived extracellular vesicles as cell‐free biologics for the ex vivo expansion of hematopoietic stem cells

“…are governed by both intrinsic (cell‐autonomous) as well as extrinsic (non‐cell‐autonomous) niche factors (Saleh et al, 2015). However, despite the vast literature available, still very little is known about the critical cell types and growth factors engaged in communication between HSCs and the niche owing to challenges involved in modeling this network (Tajer et al, 2019). We think that developing novel approaches in overcoming such difficulties would be crucial towards improving HSC expansion strategies for clinical applications.…”

“…Improved understanding regarding the cellular and molecular (intercellular) communication between the HSCs and the BM niche has provided additional insights into how the HSC self‐renewal is regulated (Tajer et al, 2019). The BM microenvironment communicates with the HSCs through various modes of intercellular communications.…”