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Review
. 2020 Apr;1466(1):39-50.
doi: 10.1111/nyas.14133. Epub 2019 Jun 14.

Ex vivo HSC expansion challenges the paradigm of unidirectional human hematopoiesis

Affiliations
Review

Ex vivo HSC expansion challenges the paradigm of unidirectional human hematopoiesis

Luena Papa et al. Ann N Y Acad Sci. 2020 Apr.

Abstract

Understanding mechanisms that determine the behavior of human hematopoietic stem cells (HSCs) is essential for developing novel strategies to expand ex vivo the number of fully functional HSCs. In this review, we focus on the complex interplay between intrinsic mechanisms regulated by transcriptional and mitochondrial networks and extrinsic signals imposed by the bone marrow microenvironment, which in concert regulate the balance between HSC self-renewal and differentiation. Such integrated signaling mechanisms that dictate the fate of HSCs in vivo must be recapitulated ex vivo to achieve successful expansion of clinically relevant HSCs. We also highlight some of the most recent ex vivo HSC expansion strategies that have currently entered clinical development. Finally, based on the evidence reviewed here and lessons learned from ex vivo HSC expansion, we raise some critical questions regarding HSC fate and the cellular plasticity of hematopoietic cells that challenge the unidirectional model of human hematopoiesis.

Keywords: BM niches; HSCs; ex vivo expansion; mitochondrial network.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Models of hematopoiesis. (A) Classical unidirectional model of hematopoiesis. Quiescent HSCs reside in the BM niches and rely mainly on glycolysis for their energy production. Upon hematopoietic stress, HSCs exit the quiescent state and become activated into slowly dividing HSCs, giving rise to a daughter cell that may remain in the cell cycle or to a daughter cell that may return back into a quiescent state to maintain the pool of primitive HSCs. Frequent and rapid cell divisions lead to transiently amplifying progenitors, which in turn give rise to more differentiated effector hematopoietic cells. A metabolic switch associated with an increased level of mitochondrial OXPHOS activity, ROS generation, and mass occurs during the course of differentiation. (B) Hypothetical bidirectional model of hematopoiesis. Under hematopoietic stress, progenitor cells might be reprogramed and reacquire a stem‐like fate to replenish and sustain the pool of dividing HSCs with self‐renewal potential (dotted arrows).

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