Less Is More: Unveiling the Functional Core of Hematopoietic Stem Cells through Knockout Mice

Abstract

Summary Hematopoietic stem cells (HSCs) represent one of the first recognized somatic stem cells. As such, nearly 200 genes have been examined for roles in HSC function in knockout mice. In this review, we compile the majority of these reports to provide a broad overview of the functional modules revealed by these genetic analyses and highlight some key regulatory pathways involved, including cell cycle control, TGF-β signaling, Pten/AKT signaling, Wnt signaling, and cytokine signaling. Finally, we propose recommendations for characterization of HSC function in knockout mice to facilitate cross-study comparisons that would generate a more cohesive picture of HSC biology. In the field of design, the minimalist movement stripped down buildings and objects to their most basic features, a sentiment that architect Ludwig Mies van der Rohe summarized in his motto “less is more”. By depleting HSCs of specific genes, knockout studies transpose the minimalist approach into research biology, providing insights into the essential core of genetic features that is indispensable for a well-functioning hematopoietic system.

Tgif1 Regulates Quiescence and Self-Renewal of Hematopoietic Stem Cells

“…Importantly, Tgif1 affects HSC function in both the nullizygous state and the heterozygous state, while overexpression has opposite effects to loss of function in HSC populations. Tgif1 thus joins a very small list of genes whose knockdown has a positive effect and overexpression has a negative effect on HSC function (24). On the basis of its interactions with TGF-␤ and RA signaling pathways and its effects on myeloid cell functions, Tgif1 has been suggested to have a role in HSC regulation, and this study provides the first direct evidence by showing that Tgif1 has important actions in the most primitive hematopoietic stem and progenitor cells.…”

“…These cells are capable of self-renewal (thus maintaining their own number) and can differentiate into any type of blood cell, losing their capacity of self-renewal in the process (22)(23)(24). The vast majority of HSCs in the bone marrow are quiescent; i.e., they are in the G 0 phase of the cell cycle, which prevents their exhaustion and ensures a pool of self-renewing cells (25)(26)(27).…”

TGF-β signaling in the control of hematopoietic stem cells

“…To rapidly tailor blood production to acute changes, such as bleeding and infection, HSC behavior is tightly regulated yet highly flexible. 4 Signals that promote quiescence, and cues that stimulate proliferation and differentiation, provide a finebalanced system that safeguards against depletion and overproduction of HSCs. Disruption of these regulatory mechanisms can result in blood disease, such as BM failure or leukemia.…”

The analysis, roles and regulation of quiescence in hematopoietic stem cells

“…Highly dormant HSCs identified by label retention of H2B-GFP exhibit higher repopulation potentials in sublethal irradiation transplantation compared with cycling HSCs (Foudi et al, 2009;Wilson et al, 2008). Consistently, the majority of gene knockout mice with HSC defects suggest that excessive proliferation and loss of quiescence results in defective HSC repopulation (Rossi et al, 2012) implying the existence of cell-autonomous, intrinsic regulatory mechanisms that link quiescence to the repopulating potential of HSCs. However, the knockout of some genes such as Fig.…”

“…+ populations in the human bone marrow (Danet et al, 2002;Notta et al, 2011 The stem cell potential, or 'stemness' of HSCs relies upon a combination of properties: quiescence, repopulation potential, selfrenewal potential and multi-lineage differentiation potential (Rossi et al, 2012). The repopulation potential of HSCs can be assessed through competitive bone marrow transplantation with myeloablative conditioning; this approach is considered to be the golden standard of assessment.…”