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The hematopoietic stem cell (HSC) forms all types of blood cells of the hematopoietic system. In the adult, HSC are mainly quiescent, being mostly in G0/G1 phase of cell cycle during steady-state conditions. However, during hematopoietic stress, the stem cells respond quickly to regenerate the damaged hematopoietic system. To understand how environmental signals affect HSC and its progeny, it is essential to know the lineage relationships and transcriptional mechanisms controlling self-renewal, proliferation and differentiation. Because of the high possible output of blood cells from a single HSC, a tight regulation of these processes is extremely important. An essential component for this control is the marrow microenvironment, in this context also referred to as the HSC niche. The niche is heterogeneous and regulates stem cell metabolism through both surface-bound and soluble factors. Several signaling pathways have been shown to take part in these regulation processes, with Notch and especially Wnt signaling being the best studied ones. Dysregulation of the niche, for instance by environmental exposure, has recently been shown to lead to hematopoietic abnormalities. Thus, to understand the effect of the environment on hematopoiesis, it is of importance to study both HSC, its direct progeny and the cellular components of the niche. Detailed knowledge of the regulatory mechanisms operating between hematopoietic cells and their direct surroundings facilitates the study of how such signaling may be disrupted by environmental exposure.

Pleiotrophin (Ptn) is strongly expressed by stromal cells which maintain HSCs. However, in vivo, Ptn deficiency does not alter steady-state hematopoiesis. However, knockdown of Ptn (PtnKD) in stromal cells increases production of hematopoietic progenitors as well as HSC activity in cocultures, suggesting that Ptn may have a role in HSC activation. Indeed, transplantations of wild-type (Ptn+/+) HSCs into Ptn−/− mice show increased donor cell production in serial transplantations and dominant myeloid regeneration caused by Ptn-dependent regulation of HSC repopulation behavior. This regulation of Lin−Kit+Sca1+ function is associated with increased proliferation and, on a molecular level, with up-regulated expression of cyclin D1 (Ccnd1) and C/EBPα (Cepba), but reduced of PPARγ. The known HSC regulator β-catenin is, however, not altered in the absence of Ptn. In conclusion, our results point to different Ptn-mediated regulatory mechanisms in normal hemostasis and in hematopoietic regeneration and in maintaining the balance of myeloid and lymphoid regeneration. Moreover, our results support the idea that microenvironmental Ptn regulates hematopoietic regeneration through β-catenin–independent regulation of Ccnd1 and Cebpa.

Summary Secreted frizzled-related protein 1 ( Sfrp1 ) is highly expressed by stromal cells maintaining hematopoietic stem cells (HSCs). Sfrp1 loss in stromal cells increases production of hematopoietic progenitors, and in knockout mice, dysregulates hemostasis and increases Flk2− Cd34− Lin− Sca1+ Kit+ (LSK) cell numbers in bone marrow. Also, LSK and multipotent progenitors (MPPs) resided mainly in the G0/G1 phase of cell cycle, with an accompanying decrease in intracellular β-catenin levels. Gene-expression studies showed a concomitant decrease Ccnd1 and Dkk1 in Cd34− LSK cells and increased expression of Pparg , Hes1 , and Runx1 in MPP. Transplantation experiments showed no intrinsic effect of Sfrp1 loss on the number of HSCs or their ability to engraft irradiated recipients. In contrast, serial transplantations of wild-type HSCs into Sfrp1 −/− mice show a progressive decrease of wild-type LSK and MPP numbers. Our results demonstrate that Sfrp1 is required to maintain HSC homeostasis through extrinsic regulation of β-catenin.