Title: Detection of aberrant hippocampal mossy fiber connections: Ex vivo mesoscale diffusion MRI and microtractography with histological validation in a patient with uncontrolled temporal lobe epilepsy
Authors: Vasudeva K, Vodovotz Y, Azhar N, Barclay D, Janjic JM, Pollock JA.
Title: In vivo and systems biology studies implicate IL-18 as a central mediator in chronic pain.
Summary: Inflammation is associated with peripheral neuropathy, however the interplay among cytokines, chemokines, and neurons is still unclear. We hypothesized that this neuroinflammatory interaction can be defined by computational modeling based on the dynamics of protein expression in the sciatic nerve of rats subjected to chronic constriction injury. Using Dynamic Bayesian Network inference, we identified interleukin (IL)-18 as a central node associated with neuropathic pain in this animal model. Immunofluorescence supported a role for inflammasome activation and induction of IL-18 at the site of injury. Combined in vivo and in silico approaches may thus highlight novel targets in peripheral neuropathy.
Authors: Brown D, Namas RA, Almahmoud K, Zaaqoq A, Sarkar J, Barclay DA, Yin J, Ghuma A, Abboud A, Constantine G, Nieman G, Zamora R, Chang SC, Billiar TR, Vodovotz Y.
Title: Trauma in silico: Individual-specific mathematical models and virtual clinical populations
Summary: Trauma-induced critical illness is driven by acute inflammation, and elevated systemic interleukin-6 (IL-6) after trauma is a biomarker of adverse outcomes. We constructed a multicompartment, ordinary differential equation model that represents a virtual trauma patient. Individual-specific variants of this model reproduced both systemic inflammation and outcomes of 33 blunt trauma survivors, from which a cohort of 10,000 virtual trauma patients was generated. Model-predicted length of stay in the intensive care unit, degree of multiple organ dysfunction, and IL-6 area under the curve as a function of injury severity were in concordance with the results from a validation cohort of 147 blunt trauma patients. In a subcohort of 98 trauma patients, those with high-IL-6 single-nucleotide polymorphisms (SNPs) exhibited higher plasma IL-6 levels than those with low IL-6 SNPs, matching model predictions. Although IL-6 could drive mortality in individual virtual patients, simulated outcomes in the overall cohort were independent of the propensity to produce IL-6, a prediction verified in the 98-patient subcohort. In silico randomized clinical trials suggested a small survival benefit of IL-6 inhibition, little benefit of IL-1Î² inhibition, and worse survival after tumor necrosis factor-Î± inhibition. This study demonstrates the limitations of extrapolating from reductionist mechanisms to outcomes in individuals and populations and demonstrates the use of mechanistic simulation in complex diseases.
Authors: Syed-Picard FN, Du Y, Lathrop KL, Mann MM, Funderburgh ML, Funderburgh JL
Title: Dental pulp stem cells: a new cellular resource for corneal stromal regeneration
Summary: Corneal blindness afflicts millions of individuals worldwide and is currently treated by grafting with cadaveric tissues; however, there are worldwide donor tissue shortages, and many allogeneic grafts are eventually rejected. Autologous stem cells present a prospect for personalized regenerative medicine and an alternative to cadaveric tissue grafts. Dental pulp contains a population of adult stem cells and, similar to corneal stroma, develops embryonically from the cranial neural crest. We report that adult dental pulp cells (DPCs) isolated from third molars have the capability to differentiate into keratocytes, cells of the corneal stoma. After inducing differentiation in vitro, DPCs expressed molecules characteristic of keratocytes, keratocan, and keratan sulfate proteoglycans at both the gene and the protein levels. DPCs cultured on aligned nanofiber substrates generated tissue-engineered, corneal stromal-like constructs, recapitulating the tightly packed, aligned, parallel fibrillar collagen of native stromal tissue. After injection in vivo into mouse corneal stroma, human DPCs produced corneal stromal extracellular matrix containing human type I collagen and keratocan and did not affect corneal transparency or induce immunological rejection. These findings demonstrate a potential for the clinical application of DPCs in cellular or tissue engineering therapies for corneal stromal blindness.
Authors: Sayan Basu, Andrew J. Hertsenberg, Martha L. Funderburgh, Michael K. Burrow, Mary M. Mann, Yiqin Du, Kira L. Lathrop, Fatima N. Syed-Picard, Sheila M. Adams, David E. Birk, James L. Funderburgh.
Title: Human limbal biopsyâ€“derived stromal stem cells prevent corneal scarring
Summary: Our corneasâ€”transparent, collagen-based structures that allow us to seeâ€”are easily damaged by trauma and infection, resulting in scarring and, in many cases, blindness. Although corneal transplant is the clinical norm, adverse immune responses and a shortage of cornea donors are serious limitations. Basu and colleagues devised a personalized cell-based, nonsurgical approach to prevent corneal scarring. They obtained mesenchymal stem cells from the human limbus (the region between the cornea and the sclera) and confirmed that they could be differentiated into keratocytes (corneal cells) in vitro. The human limbal biopsyâ€“derived stromal cells, or LBSCs, were then placed in a fibrin gel and applied to the surface of debridement wounds in mice. The LBSCs were able to regenerate damaged stromal tissue in the animals, resembling native corneal tissue. Because these cells can be obtained directly from the patient and because fibrin-based products are already used in people, this approach could translate soon to treat stromal scarring, a major cause of corneal blindness.
Authors: Pratyush Dayal, Olga Kuksenok, and Anna C. Balazs.
Title: Directing the Behavior of Active, Self-Oscillating Gels with Light
Summary: In the biological realm, light can act as a powerful stimulus, promoting both positive and negative phototaxis. Using computational modeling, we attempt to design systems that display analogous biomimetic behavior by exhibiting directed, autonomous motion in response to light. We specifically focus on polymer gels that undergo the oscillating Belousovâ€“Zhabotinsky (BZ) reaction and thus manifest periodic chemomechanical pulsations, which can be modulated with light. Reviewing our recent computational studies, we describe how long, rectangular samples of BZ gels, or â€œwormsâ€, can perform self-sustained movement and via a distinct form of negative phototaxis migrate along complex paths under nonuniform illumination. When the ends of multiple rectangular BZ gels are anchored to a surface, the dynamic behavior of the cilia-like layer can be tuned by light to resemble the motion of a keyboard. With BZ gel pieces that move freely on a surface, we show that these gels exhibit autochemotaxis and, thereby, can self-organize in response to self-generated chemical signals. These examples illustrate that BZ gels constitute optimal materials for creating millimeter-sized soft robots whose self-sustained movement can be regulated through the use of light.
Authors: Dutta-Moscato J, Solovyev A, Mi Q, Nishikawa T, Soto-Gutierrez A, Fox IJ, Vodovotz Y.
Title: A multiscale agent-based in silico model of liver fibrosis progression.
Summary: Chronic hepatic inflammation involves a complex interplay of inflammatory and mechanical influences, ultimately manifesting in a characteristic histopathology of liver fibrosis. We created an agent-based model (ABM) of liver tissue in order to computationally examine the consequence of liver inflammation. Our liver fibrosis ABM (LFABM) is comprised of literature-derived rules describing molecular and histopathological aspects of inflammation and fibrosis in a section of chemically injured liver. Hepatocytes are modeled as agents within hexagonal lobules. Injury triggers an inflammatory reaction, which leads to activation of local Kupffer cells and recruitment of monocytes from circulation. Portal fibroblasts and hepatic stellate cells are activated locally by the products of inflammation. The various agents in the simulation are regulated by above-threshold concentrations of pro- and anti-inflammatory cytokines and damage-associated molecular pattern molecules. The simulation progresses from chronic inflammation to collagen deposition, exhibiting periportal fibrosis followed by bridging fibrosis, and culminating in disruption of the regular lobular structure. The ABM exhibited key histopathological features observed in liver sections from rats treated with carbon tetrachloride (CCl4). An in silico â€œtension testâ€ for the hepatic lobules predicted an overall increase in tissue stiffness, in line with clinical elastography literature and published studies in CCl4-treated rats. Therapy simulations suggested differential anti-fibrotic effects of neutralizing tumor necrosis factor alpha vs. enhancing M2 Kupffer cells. We conclude that a computational model of liver inflammation on a structural skeleton of physical forces can recapitulate key histopathological and macroscopic properties of CCl4-injured liver. This multiscale approach linking molecular and chemomechanical stimuli enables a model that could be used to gain translationally relevant insights into liver fibrosis.
Authors: Lui VW, Peyser ND, Ng PK, Hritz J, Zeng Y, Lu Y, Li H, Wang L, Gilbert BR, General IJ, Bahar I, Ju Z, Wang Z, Pendleton KP, Xiao X, Du Y, Vries JK, Hammerman PS, Garraway LA, Mills GB, Johnson DE, Grandis JR.
Title: Frequent mutation of receptor protein tyrosine phosphatases provides a mechanism for STAT3 hyperactivation in head and neck cancer.
Title: Potential Barriers to Human Hepatocyte Transplantation in MUP-uPAtg (+/+)Rag2-/-?C-/- Mice
Summary: Primary human fetal and adult hepatocytes have been considered feasible donor cell sources for cell transplantation. We compared the engraftment efficiencies between adult human, fetal human, and adult porcine hepatocytes after transplantation into MUP-uPAtg (+/+)Rag2-/-?C-/- mice. Transplantation of adult human hepatocytes yielded a thousand-fold higher serum albumin level compared to transplantation of fetal human hepatocytes, while transplantation of adult porcine hepatocytes resulted in a hundred-fold higher serum albumin level than adult human hepatocytes. These results suggest that adult liver cells are superior to fetal liver cells for transplantation, and caution should be applied if porcine hepatocytes are used for preclinical studies as a proof of concept for human hepatocytes.