Key Points• Normally, engrafting HSCs reside and oscillate within confined bone marrow niches.• HSCs harvested from mice bearing acute infection are migratory and interact with larger niches.Hematopoietic stem cells (HSCs) maintain the turnover of mature blood cells during steady state and in response to systemic perturbations such as infections. Their function critically depends on complex signal exchanges with the bone marrow (BM) microenvironment in which they reside, but the cellular mechanisms involved in HSC-niche interactions and regulating HSC function in vivo remain elusive. We used a natural mouse parasite, Trichinella spiralis, and multipoint intravital time-lapse confocal microscopy of mouse calvarium BM to test whether HSC-niche interactions may change when hematopoiesis is perturbed. We find that steady-state HSCs stably engage confined niches in the BM whereas HSCs harvested during acute infection are motile and therefore interact with larger niches. These changes are accompanied by increased long-term repopulation ability and expression of CD44 and CXCR4. Administration of a CXCR4 antagonist affects the duration of HSC-niche interactions. These findings suggest that HSC-niche interactions may be modulated during infection. IntroductionThe function of hematopoietic stem cells (HSCs) depends on their interaction with complex niches within the bone marrow (BM) 1,2 and must readily adjust to meet the changing needs for differentiated cells during situations of stress, such as the immune responses generated by infectious agents.3-5 The current working hypothesis is that changes in HSC-niche interactions may cause changes in HSC function and therefore a major challenge in the field is to understand the specific cellular behaviors (eg, duration of cell-cell/cell-matrix interactions) resulting in different HSC fates (quiescence vs proliferation, self-renewal vs differentiation). Direct visualization of HSCs in vivo and over time is the ideal approach to monitor the nature of the cellular interactions between individual stem cells and their niches and can be achieved by intravital microscopy of mouse calvarium BM. 6,7 We studied a naturally occurring, nonlethal mouse model of infection initiated by ingestion of the parasitic nematode Trichinella spiralis, the infectious agent causing trichinosis. Ingested T spiralis reside for several days in the intestinal epithelium, where they mature, proliferate, and release larvae, which migrate into the circulatory system and invade the skeletal muscle, where they form cysts and survive for the life of the host.8 Migration of parasites causes extensive tissue damage and intense inflammation over the early phase of infection (weeks 1-3), which is ameliorated by the induction of regulatory cytokines during the chronic phase of the disease. 9,10Here we show that acute T spiralis infection affects hematopoietic dynamics and boosts HSC function. Using time-lapse intravital microscopy of transplanted HSCs, we show that acute infection is accompanied by changes in HSC-nic...

Our approach provides new insights into organization of MSC populations in vitro. The results suggest that MSC differentiation is largely reversible and that lineage plasticity is restricted to stem cells and early progenitors. The model predicts a significant impact of short-term low oxygen treatment on MSC differentiation and optimal chondrogenic differentiation at 10-11% pO(2).

BackgroundHematopoiesis is a complex process involving different cell types and feedback mechanisms mediated by cytokines. This complexity stimulated various models with different scopes and applications. A combination of complementary models promises to provide their mutual confirmation and to explain a broader range of scenarios. Here we propose a combination of an ordinary differential equation (ODE) model of human granulopoiesis and an agent-based model (ABM) of hematopoietic stem cell (HSC) organization. The first describes the dynamics of bone marrow cell stages and circulating cells under various perturbations such as G-CSF treatment or chemotherapy. In contrast to the ODE model describing cell numbers, our ABM focuses on the organization of individual cells in the stem population.ResultsWe combined the two models by replacing the HSC compartment of the ODE model by a difference equation formulation of the ABM. In this hybrid model, regulatory mechanisms and parameters of the original models were kept unchanged except for a few specific improvements: (i) Effect of chemotherapy was restricted to proliferating HSC and (ii) HSC regulation in the ODE model was replaced by the intrinsic regulation of the ABM. Model simulations of bleeding, chronic irradiation and stem cell transplantation revealed that the dynamics of hybrid and ODE model differ markedly in scenarios with stem cell damage. Despite these differences in response to stem cell damage, both models explain clinical data of leukocyte dynamics under four chemotherapy regimens.ConclusionsABM and ODE model proved to be compatible and were combined without altering the structure of both models. The new hybrid model introduces model improvements by considering the proliferative state of stem cells and enabling a cell cycle-dependent effect of chemotherapy. We demonstrated that it is able to explain and predict granulopoietic dynamics for a large variety of scenarios such as irradiation, bone marrow transplantation, chemotherapy and growth factor applications. Therefore, it promises to serve as a valuable tool for studies in a broader range of clinical applications, in particular where stem cell activation and proliferation are involved.