Visualizing hematopoiesis as a stochastic process.

Stochastic simulation has played an important role in understanding hematopoiesis, but implementing and interpreting mathematical models requires a strong statistical background, often preventing their use by many clinical and translational researchers. Here, we introduce a user-friendly graphical interface with capabilities for visualizing hematopoiesis as a stochastic process, applicable to a variety of mammal systems and experimental designs. We describe the visualization tool and underlying mathematical model, and then use this to simulate serial transplantations in mice, human cord blood cell expansion, and clonal hematopoiesis of indeterminate potential.

Discovering early diabetic neuropathy from epidermal nerve fiber patterns.

Epidermal nerve fibre (ENF) density and morphology are used to study small fibre involvement in diabetic, HIV, chemotherapy induced and other neuropathies. ENF density and summed length of ENFs per epidermal surface area are reduced, and ENFs may appear more clustered within the epidermis in subjects with small fibre neuropathy than in healthy subjects. Therefore, it is important to understand the spatial structure of ENFs.

Likelihood-based inference for discretely observed birth-death-shift processes, with applications to evolution of mobile genetic elements.

Continuous-time birth-death-shift (BDS) processes are frequently used in stochastic modeling, with many applications in ecology and epidemiology. In particular, such processes can model evolutionary dynamics of transposable elements-important genetic markers in molecular epidemiology. Estimation of the effects of individual covariates on the birth, death, and shift rates of the process can be accomplished by analyzing patient data, but inferring these rates in a discretely and unevenly observed setting presents computational challenges.

The replication rate of human hematopoietic stem cells in vivo.

Hematopoietic stem cells (HSCs) replicate (self-renew) to create 2 daughter cells with capabilities equivalent to their parent, as well as differentiate, and thus can both maintain and restore blood cell production. Cell labeling with division-sensitive markers and competitive transplantation studies have been used to estimate the replication rate of murine HSCs in vivo. However, these methods are not feasible in humans and surrogate assays are required.

BAYESIAN INFERENCE AND MODEL CHOICE IN A HIDDEN STOCHASTIC TWO-COMPARTMENT MODEL OF HEMATOPOIETIC STEM CELL FATE DECISIONS.

Despite rapid advances in experimental cell biology, the in vivo behavior of hematopoietic stem cells (HSC) cannot be directly observed and measured. Previously we modeled feline hematopoiesis using a two-compartment hidden Markov process that had birth and emigration events in the first compartment. Here we perform Bayesian statistical inference on models which contain two additional events in the first compartment in order to determine if HSC fate decisions are linked to cell division or occur independently.

Hematopoietic stem-cell behavior in nonhuman primates.

Little is known about the behavior of hematopoietic stem cells (HSCs) in primates because direct observations and competitive-repopulation assays are not feasible. Therefore, we used 2 different and independent experimental strategies, the tracking of transgene expression after retroviral-mediated gene transfer (N = 11 baboons; N = 7 rhesus macaques) and quantitation of the average telomere length of granulocytes (N = 132 baboons; N = 14 macaques), together with stochastic methods, to study HSC kinetics in vivo. The average replication rate for baboon HSCs is once per 36 weeks according to gene-marking analyses and once per 23 weeks according to telomere-shortening analyses.

The kinetics of clonal dominance in myeloproliferative disorders.

To study clonal evolution in myeloproliferative disorders, we used stochastic models of hematopoiesis for mouse and cat, species for which the in vivo kinetics of hematopoietic stem cells (HSCs) have been experimentally defined. We determined the consequence if 1 HSC became able to survive without the support of a microenvironmental niche while the rest of its behavior did not change. Neoplastic cells persisted and dominated hematopoiesis in 14% of mice and 17% of cats, requiring mean times of 2.

Estimating human hematopoietic stem cell kinetics using granulocyte telomere lengths.

Objective: To study in vivo behavior of hematopoietic stem cells (HSC).

Materials And Methods: Behavior of HSC is difficult to study because one cannot observe and track cells within the marrow microenvironment. Therefore, information must be obtained from indirect means, such as competitive repopulation assays or surrogate studies, such as observations of telomere shortening in granulocytes.

Strategies to expand transduced hematopoietic stem cells in vivo.

Data in mice suggest that in vivo selection strategies will expand the numbers of transduced hematopoietic stem cells (HSC) to levels sufficient for clinical therapies, and it is argued that comparable strategies will benefit larger animals and humans. To test this assumption, we performed virtual gene therapy in mouse and cat, species in which the in vivo kinetics of HSC are defined. In the simulated experiments, 10% of HSC and 50% of short-term repopulating cells were transduced with a gene allowing a conditional replication or apoptosis advantage.

Evidence that the number of hematopoietic stem cells per animal is conserved in mammals.

Humans and larger mammals require more blood cells per lifetime than mice because of their larger size and longer life expectancy. To investigate this evolutionary adaptation, we calculated the total number of nucleated marrow cells (NMCs) per cat, observing the distribution of (59)Fe to marrow, then multiplied this value (1.9 +/- 0.