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.

Lifelong, many somatic tissues are replenished by specialized adult stem cells. These stem cells are generally rare, infrequently dividing, occupy a unique niche, and can rapidly respond to injury to maintain a steady tissue size. Despite these commonalities, few shared regulatory mechanisms have been identified. Here, we scrutinized data comparing genes expressed in murine long-term hematopoietic stem cells with their differentiated counterparts and observed that a disproportionate number were members of the developmentally-important, monoallelically expressed imprinted genes. Studying a subset, which are members of a purported imprinted gene network (IGN), we found their expression in HSCs rapidly altered upon hematopoietic perturbations. These imprinted genes were also predominantly expressed in stem/progenitor cells of the adult epidermis and skeletal muscle in mice, relative to their differentiated counterparts. The parallel down-regulation of these genes postnatally in response to proliferation and differentiation suggests that the IGN could play a mechanistic role in both cell growth and tissue homeostasis.

A protein that is thought to orchestrate the distribution of other signaling molecules on the cell membrane, CD81, is critical to maintaining the functional integrity of hematopoietic stem cells during their regeneration.

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The proliferation and differentiation of adult stem cells is balanced to ensure adequate generation of differentiated cells, stem cell homeostasis, and guard against malignant transformation. CD48 is broadly expressed on hematopoietic cells but excluded from quiescent longterm murine HSCs. Through its interactions with CD244 on progenitor cells, it influences HSC function by altering the BM cytokine milieu, particularly IFN␥. In CD48-null mice, the resultant misregulation of cytokine signaling produces a more quiescent HSC, a disproportionate number of short-term progenitors, and hyperactivation of Pak1, leading to hematologic malignancies similar to those found in patients with X-linked lymphoproliferative disease. CD48 plays a vital role as an environmental sensor for regulating HSC and progenitor cell numbers and inhibiting tumor development. (Blood. 2011;118(1):80-87) IntroductionHSCs maintain lifelong blood production, but the mechanisms regulating them remain largely obscure. Although several genes have been identified that play key cell-autonomous roles in the HSC, [1][2][3][4] we still have few insights into the manner in which the BM milieu impacts HSC function. Under normal circumstances, the majority of HSCs reside in a quiescent state, with less than 5% in cycle at any given time. 5,6 Nevertheless, blood homeostasis is exquisitely effective, in that the progenitor pool and numbers of differentiated blood cells are maintained at a constant level. To ensure coordinated blood cell production, a sensitive feedback mechanism must be in place, so that the number of progeny are sensed by more primitive progenitors allowing for subtle regulation of the HSCs to generate more downstream cells only as needed. Moreover, under hematopoietic stress, the manufacture of differentiated cells is rapidly adjusted, marshaling increased output from both committed progenitors as well as HSCs. 7 When the loss of blood cells and committed progenitors is particularly complete, virtually all of the HSCs are transiently drafted, after which most of them return to quiescence to ensure long-term maintenance of the HSC pool. 6 CD48 was previously identified as broadly expressed on differentiated hematopoietic cells, but excluded from quiescent long-term HSCs (LT-HSCs). 3,8 CD48 is a GPI-linked member of the signaling lymphocyte activation molecule (SLAM) family of proteins. It can act as a ligand for SLAM member CD244 and, depending on the context, either inhibits or stimulates IFN␥ production from the target cell. 9-12 IFN␥ has previously been shown it to be a suppressor of hematopoiesis and at high levels it may lead to BM failure. 13 However, IFN␥ has also been shown to stimulate progenitor cell proliferation. [14][15][16] Recently, work from our laboratory has shown a lack of IFN␥ in vivo leads to a less proliferative HSC, whereas increasing IFN␥ increases HSC proliferation. 7 Because CD48 offered a context-dependent mechanism for the secretion of IFN␥, which impinges directly on HSCs, we sought to determine its role in maint...