HSC Niche Dynamics in Regeneration, Pre-malignancy, and Cancer: Insights From Mathematical Modeling.

The hematopoietic stem cell (HSC) niche is a crucial driver of regeneration and malignancy. Its interaction with hematopoietic and malignant stem cells is highly complex and direct experimental observations are challenging. We here develop a mathematical model which helps relate processes in the niche to measurable changes of stem and non-stem cell counts. HSC attached to the niche are assumed to be quiescent. After detachment HSC become activated and divide or differentiate. To maintain their stemness, the progeny originating from division must reattach to the niche. We use mouse data from literature to parametrize the model. By combining mathematical analysis and computer simulations, we systematically investigate the impact of stem cell proliferation, differentiation, niche attachment, and detachment on clinically relevant scenarios. These include bone marrow transplantation, clonal competition, and eradication of malignant cells. According to our model, sampling of blood or bulk marrow provides only limited information about cellular interactions in the niche and the clonal composition of the stem cell population. Furthermore, we investigate how interference with processes in the stem cell niche could help to increase the effect of low-dose chemotherapy or to improve the homing of genetically engineered cells.

Temperate climate malaria in nineteenth century Denmark.

BACKGROUND: Plasmodium vivax was endemic in northern Europe until the early twentieth century. Considering climate change and the recent emergence of other vector borne diseases in Europe, historical insight into the relationship between malaria and environmental factors in northern Europe is needed. This article describes malaria epidemiology in late-nineteenth century Denmark. METHODS: We described the seasonality and spatial patterns of malaria, and the relationship of the disease with environmental factors such as soil types, clay content and elevation for the period 1862-1914. We studied demographic and seasonal patterns and malaria mortality in the high-morbidity period of 1862-1880. Finally, we studied the relationship between malaria seasonality and temperature and precipitation using a Spearman correlation test. RESULTS: We found that the highest incidence occurred in eastern Denmark. Lolland-Falster medical region experienced the highest incidence (14.5 cases per 1000 pop.) and Bornholm medical region experienced the lowest incidence (0.57 cases per 1000 pop.). Areas with high malaria incidence also had high soil clay content, high agricultural production, and Lolland-Falster furthermore has a low elevation. Malaria incidence typically peaked in May and was associated with high temperatures in July and August of the previous year but not with precipitation. The case fatality rate was 0.17%, and the disease affected both sexes and all age groups except for infants. In 1873, a large epidemic occurred following flooding from a storm surge in November 1872. CONCLUSIONS: Malaria gradually declined in Denmark during our study period and had essentially disappeared by 1900. The high adult and low child morbidity in 1862-1880 indicates that malaria was not highly endemic in this period, as malaria is most frequent among children in highly endemic areas today. The association of high malaria incidence in spring with warmer temperatures in the previous summer suggests that transmission took place in the previous summers. The close geographical connection between malaria and soil types, agricultural production and elevation suggests that these factors are detrimental to sustain endemic malaria. Our findings of a close connection between malaria and environmental factors such as climate and geography provides insights to address potential reintroduction of malaria in temperate climates.

Mathematical modelling of the hematopoietic stem cell-niche system: Clonal dominance based on stem cell fitness.

Human blood cell production is maintained by hematopoietic stem cells (HSC) which give rise to all types of mature blood cells. Experimental observation of HSC in their physiologic bone-marrow microenvironment, the so-called stem cell niche, is challenging. Therefore, the details of HSC dynamics and the cellular interactions in the stem cell niche remain elusive. Mutations that lead to a competitive advantage are the cause of clinical challenges when treating HSC-derived malignancies such as acute myeloid leukemia or the myeloproliferative neoplasms (MPNs). To investigate the significance of the interaction between the HSC and the stem cell niche in these malignancies, we propose and analyse a mechanism-based mathematical model of HSC dynamics within the bone-marrow microenvironment. The model is based on the central hypothesis that HSC self-renewal depends on the niche. In the model, the interaction of HSC with specific niches located in the bone marrow are key to the indefinite HSC renewal necessary for long-term maintenance of blood cell production. We formulate a general model of n distinct clones that differ with respect to cell properties. We identify an attractive trapping region and compute and classify all steady states. A concept of HSC fitness naturally arises from the model analysis. HSC fitness is found to determine the asymptotic behaviour of the model, as the HSC clone with the highest fitness is related to the unique locally stable steady state. Based on biological assumptions about HSC, we propose two reduced models of different complexity. A thorough mathematical analysis reveals that both reduced models have the same asymptotic behaviour as the full model. We compare the simpler of the two models, a logistic equation of the disease burden, to clinical data of MPN-patients. The reduced model is found to agree well with data and suggests a simple interpretation and possible prediction of patient prognosis. The proposed mathematical model and the reduced forms have the potential to provide insights into the regulation of HSC dynamics and blood cell formation, and ultimately for future advances in treatment of hematologic malignancies.