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.