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MSTPublications: December 2018

Posted by on Wednesday, December 19, 2018 in New Publications.

Bone Marrow–Derived Proangiogenic Cells Mediate Pulmonary Arteriole Stiffening via Serotonin 2B Receptor Dependent Mechanism
Bloodworth NC, Clark CR, West JD, Snider C, Gaskill C, Shay S, Scott C, Bastarache J, Gladson S, Moore C, D’Amico R, Brittain EL, Tanjore H, Blackwell TS, Majka SM, Merryman WD.
Circ Res. Originally published 2018 Oct 25;123:e51–e64. doi:10.1161/CIRCRESAHA.118.31339

Rationale: Pulmonary arterial hypertension is a deadly disease of the pulmonary vasculature for which no disease-modifying therapies exist. Small-vessel stiffening and remodeling are fundamental pathological features of pulmonary arterial hypertension that occur early and drive further endovascular cell dysfunction. Bone marrow (BM)–derived proangiogenic cells (PACs), a specialized heterogeneous subpopulation of myeloid lineage cells, are thought to play an important role in pathogenesis. Objective: To determine whether BM-derived PACs directly contributed to experimental pulmonary hypertension (PH) by promoting small-vessel stiffening through 5-HT2B (serotonin 2B receptor)–mediated signaling. Methods and Results: We performed BM transplants using transgenic donor animals expressing diphtheria toxin secondary to activation of an endothelial-specific tamoxifen-inducible Cre and induced experimental PH using hypoxia with SU5416 to enhance endovascular injury and ablated BM-derived PACs, after which we measured right ventricular systolic pressures in a closed-chest procedure. BM-derived PAC lineage tracing was accomplished by transplanting BM from transgenic donor animals with fluorescently labeled hematopoietic cells and treating mice with a 5-HT2B antagonist. BM-derived PAC ablation both prevented and reversed experimental PH with SU5416-enhanced endovascular injury, reducing the number of muscularized pulmonary arterioles and normalizing arteriole stiffness as measured by atomic force microscopy. Similarly, treatment with a pharmacological antagonist of 5-HT2B also prevented experimental PH, reducing the number and stiffness of muscularized pulmonary arterioles. PACs accelerated pulmonary microvascular endothelial cell injury response in vitro, and the presence of BM-derived PACs significantly correlated with stiffer pulmonary arterioles in pulmonary arterial hypertension patients and mice with experimental PH. RNA sequencing of BM-derived PACs showed that 5-HT2B antagonism significantly altered biologic pathways regulating cell proliferation, locomotion and migration, and cytokine production and response to cytokine stimulus. Conclusions: Together, our findings illustrate that BM-derived PACs directly contribute to experimental PH with SU5416-enhanced endovascular injury by mediating small-vessel stiffening and remodeling in a 5-HT2B signaling–dependent manner.

 

Human islets expressing HNF1A variant have defective β cell transcriptional regulatory networks.
Haliyur R, Tong X, Sanyoura M, Shrestha S, Lindner J, Saunders DC, Aramandla R, Poffenberger G, Redick SD, Bottino R, Prasad N, Levy SE, Blind RD, Harlan DM, Philipson LH, Stein RW, Brissova M, Powers AC.
J Clin Invest. 2018 Dec 3. pii: 121994. doi: 10.1172/JCI121994. [Epub ahead of print]

Using an integrated approach to characterize the pancreatic tissue and isolated islets from a 33-year-old with 17 years of type 1 diabetes (T1D), we found that donor islets contained β cells without insulitis and lacked glucose-stimulated insulin secretion despite a normal insulin response to cAMP-evoked stimulation. With these unexpected findings for T1D, we sequenced the donor DNA and found a pathogenic heterozygous variant in the gene encoding hepatocyte nuclear factor-1α (HNF1A). In one of the first studies of human pancreatic islets with a disease-causing HNF1A variant associated with the most common form of monogenic diabetes, we found that HNF1A dysfunction leads to insulin-insufficient diabetes reminiscent of T1D by impacting the regulatory processes critical for glucose-stimulated insulin secretion and suggest a rationale for a therapeutic alternative to current treatment.

 

Gestational Age at Arrest of Development: An Alternative Approach for Assigning Time at Risk in Studies of Time-Varying Exposures and Miscarriage.
Sundermann AC, Mukherjee S, Wu P, Velez Edwards DR, Hartmann KE.
Am J Epidemiol. 2018 Dec 6. doi: 10.1093/aje/kwy267. [Epub ahead of print]

Time between arrest of pregnancy development and miscarriage represents a window in which pregnancy is nonviable and not developing. In effect, the loss has happened and exposures cannot influence its fate. However, epidemiologic studies of miscarriage traditionally use gestational age at miscarriage to assign time in survival analyses, which overestimates duration of exposure and time at risk. In the Right from the Start pregnancy cohort (2000-2012), we characterized the gap between estimated gestational age at arrest of development (GAAD) and miscarriage using transvaginal ultrasound in 500 women recruited from 3 states (North Carolina, Tennessee, and Texas). We compare effect estimates from models using GAAD versus gestational age at miscarriage to assign time at risk through a simulation study of 4 exposure patterns with varying effect sizes. The median gap between GAAD and miscarriage was 23 days (inter-quartile range 15-32 days). Use of GAAD decreased bias and variance of the estimated association for time-varying exposures, whereas half the time using gestational age at miscarriage led to estimates that differed from the true effect by more than 20%. Using GAAD to assign time at risk should result in more accurate and consistent characterization of miscarriage risk associated with time-varying exposures.

Cumulative incidence of neck recurrence with increasing depth of invasion.
Shinn JR, Wood CB, Colazo JM, Harrell FE Jr, Rohde SL, Mannion K.
Oral Oncol. 2018 Dec;87:36-42. doi: 10.1016/j.oraloncology.2018.10.015. Epub 2018 Oct 20.

Astrocyte HIF-2α supports learning in a passive avoidance paradigm under hypoxic stress.
Leiton CV, Chen E, Cutrone A, Conn K, Mellanson K, Malik DM, Klingener M, Lamm R, Cutrone M, Petrie J 4th, Sheikh J, DiBua A, Cohen B, Floyd TF.
Hypoxia (Auckl). 2018 Nov 8;6:35-56. doi: 10.2147/HP.S173589. eCollection 2018.

HMCES Maintains Genome Integrity by Shielding Abasic Sites in Single-Strand DNA.
Mohni KN, Wessel SR, Zhao R, Wojciechowski AC, Luzwick JW, Layden H, Eichman BF, Thompson PS, Mehta KPM, Cortez D.
Cell. 2018 Dec 1. pii: S0092-8674(18)31454-5. doi: 10.1016/j.cell.2018.10.055. [Epub ahead of print]
**Read more about this paper here!