A Purpose in Liquidity: Perfusing 3D Open Scaffolds Improves "Mini-gut" Morphogenesis and Longevity.

Channeling morphogenic signaling gradients intrinsic to intestinal epithelial stem cells, Nikolaev et al. (2020) optimized a three-dimensional microchip perfusion system that augments growth, maturation, and longevity of tubular intestinal enteroids. Reported in Nature, this system may ultimately pave the way to study human intestinal development and pathophysiology, perhaps for therapeutic discovery.

Grading TESI: Crypt and villus formation in tissue-engineered small intestine alters with stem/progenitor cell source.

The small intestine has a remarkable ability to enhance its absorptive and digestive surface area through the formation of villi, a process known as villification. We sought to learn whether developing mouse and human tissue-engineered small intestine (TESI) followed known developmental biology routes to villification, such as Sonic hedgehog ()/Indian hedgehog () and bone morphogenetic protein 4 ()/forkhead box F1 () signaling to identify targets to enhance the development of TESI. After generating TESI from prenatal and postnatal stem cell sources, we evaluated the effect of cell source derivation on villification with a grading scheme to approximate developmental stage.

Role of Mucosal Protrusion Angle in Discriminating between True and False Masses of the Small Bowel on Video Capsule Endoscopy.

The diagnosis of small-bowel tumors is challenging due to their low incidence, nonspecific presentation, and limitations of traditional endoscopic techniques. In our study, we examined the utility of the mucosal protrusion angle in differentiating between true submucosal masses and bulges of the small bowel on video capsule endoscopy. We retrospectively reviewed video capsule endoscopies of 34 patients who had suspected small-bowel lesions between 2002 and 2017.

Wnt signaling inhibition by monensin results in a period of Hippo pathway activation during intestinal adaptation in zebrafish.

Intestinal adaptation (IA) is a critical response to increase epithelial surface area after intestinal loss. Short bowel syndrome (SBS) may follow massive intestinal resection in human patients, particularly without adequate IA. We previously validated a model in zebrafish (ZF) that recapitulates key SBS pathophysiological features.

Short-term and long-term human or mouse organoid units generate tissue-engineered small intestine without added signalling molecules.

New Findings: What is the central question of this study? Tissue-engineered small intestine was previously generated in vivo by immediate implantation of organoid units derived from both mouse and human donor intestine. Although immediate transplantation of organoid units into patients shows promise as a potential future therapy, some critically ill patients might require delayed transplantation. What is the main finding and its importance? Unlike enteroids, which consist of isolated intestinal crypts, short- and long-term cultured organoid units are composed of epithelial and mesenchymal cells derived from mouse or human intestine.

Is less more? Laparoscopic versus open Ladd's procedure in children with malrotation.

Background: With the advent of minimally invasive techniques, laparoscopic Ladd's procedure is increasingly used to treat children with malrotation, yet evidence regarding its safety and efficacy is lacking. We hypothesize that operative and postoperative outcomes with the open technique are superior to the laparoscopic Ladd's procedure.

Methods: We conducted a 5-y retrospective chart review of all patients who underwent Ladd's procedure at our institution from 2010-2015.

Approach to the Diagnostic Workup and Management of Small Bowel Lesions at a Tertiary Care Center.

Background: Small bowel lesions (SBL) are rare, representing diagnostic and management challenges. The purpose of this cross-sectional study was to evaluate diagnostic modalities used and management practices of patients with SBL at an advanced endoscopic referral center.

Methods: We analyzed patients undergoing surgical management for SBL from 2005 to 2015 at a single tertiary care center.

Carcinoids and Capsules: A Case Series Highlighting the Utility of Capsule Endoscopy in Patients With Small Bowel Carcinoids.

Background: Neuroendocine tumors (NETs) or carcinoids arise at many different sites of the gastrointestinal tract. The small intestine is the most common site for NETs. Diagnosing small bowel carcinoids remains challenging given their non-specific presentations and the overall low incidence of small bowel tumors.

Marked stem/progenitor cell expansion occurs early after murine ileostomy: a new model.

Background: Improving treatment for short bowel syndrome requires a better understanding of how intestinal adaptation is affected by factors like mechanoluminal stimulation. We hypothesized that in mice, luminal diversion via an ileostomy would drive adaptive changes similar to those seen in human intestine after diversion while offering the opportunity to study the immediate events after resection that precede intestinal adaptation.

Materials And Methods: With Institutional Animal Care and Use Committee approval, a distal ileostomy with a long distal Hartman's was created in 9- to 14-week-old C57/B6 mice (n = 8).

Neural Crest Cell Implantation Restores Enteric Nervous System Function and Alters the Gastrointestinal Transcriptome in Human Tissue-Engineered Small Intestine.

Acquired or congenital disruption in enteric nervous system (ENS) development or function can lead to significant mechanical dysmotility. ENS restoration through cellular transplantation may provide a cure for enteric neuropathies. We have previously generated human pluripotent stem cell (hPSC)-derived tissue-engineered small intestine (TESI) from human intestinal organoids (HIOs).

Prolonged Absence of Mechanoluminal Stimulation in Human Intestine Alters the Transcriptome and Intestinal Stem Cell Niche.

Background & Aims: For patients with short-bowel syndrome, intestinal adaptation is required to achieve enteral independence. Although adaptation has been studied extensively in animal models, little is known about this process in human intestine. We hypothesized that analysis of matched specimens with and without luminal flow could identify new potential therapeutic pathways.

Fibroblast Growth Factors in the Gastrointestinal Tract: Twists and Turns.

Fibroblast growth factors (FGFs) are a family of conserved peptides that play an important role in the development, homeostasis, and repair processes of many organ systems, including the gastrointestinal tract. All four FGF receptors and several FGF ligands are present in the intestine. They play important roles in controlling cell proliferation, differentiation, epithelial cell restitution, and stem cell maintenance.

Created of Warm Blood and Nerves: Restoring an Enteric Nervous System in Organoids.

The enteric nervous system (ENS) regulates numerous gastrointestinal functions, including epithelial barrier permeability and motility. In a recent Nature Medicine study, Workman et al. (2016) propose a method for introducing human pluripotent stem cell-derived enteric neural crest cells into developing human intestinal organoids, thereby restoring ENS cell types and contractile function.

Intestinal adaptation in proximal and distal segments: Two epithelial responses diverge after intestinal separation.

Background: In short bowel syndrome, luminal factors influence adaptation in which the truncated intestine increases villus lengths and crypt depths to increase nutrient absorption. No study has evaluated the effect of adaptation within the distal intestine after intestinal separation. We evaluated multiple conditions, including Igf1r inhibition, in proximal and distal segments after intestinal resection to evaluate the epithelial effects of the absence of mechanoluminal stimulation.

BMP-SMAD-ID promotes reprogramming to pluripotency by inhibiting p16/INK4A-dependent senescence.

Fibrodysplasia ossificans progressiva (FOP) patients carry a missense mutation in ACVR1 [617G > A (R206H)] that leads to hyperactivation of BMP-SMAD signaling. Contrary to a previous study, here we show that FOP fibroblasts showed an increased efficiency of induced pluripotent stem cell (iPSC) generation. This positive effect was attenuated by inhibitors of BMP-SMAD signaling (Dorsomorphin or LDN1931890) or transducing inhibitory SMADs (SMAD6 or SMAD7).

Vascular Endothelial Growth Factor (VEGF) Bioavailability Regulates Angiogenesis and Intestinal Stem and Progenitor Cell Proliferation during Postnatal Small Intestinal Development.

Background: Vascular endothelial growth factor (VEGF) is a highly conserved, master regulatory molecule required for endothelial cell proliferation, organization, migration and branching morphogenesis. Podocoryne carnea and drosophila, which lack endothelial cells and a vascular system, express VEGF homologs, indicating potential roles beyond angiogenesis and vasculogenesis. The role of VEGF in the development and homeostasis of the postnatal small intestine is unknown.

Surgical site infections (SSIs) after stoma reversal (SR): risk factors, implications, and protective strategies.

Background: Stoma reversals (SRs) are commonly performed with potentially significant postoperative complications including surgical site infections (SSIs). Our aim was to determine the incidence and risk factors for SSIs in a large cohort of SR patients.

Design: We reviewed our institutional 2006-2011 American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database for 30-day SSIs in patients undergoing SR.

Induced pluripotent stem cells from patients with human fibrodysplasia ossificans progressiva show increased mineralization and cartilage formation.

Background: Abnormal activation of endochondral bone formation in soft tissues causes significant medical diseases associated with disability and pain. Hyperactive mutations in the bone morphogenetic protein (BMP) type 1 receptor ACVR1 lead to fibrodysplasia ossificans progressiva (FOP), a rare genetic disorder characterized by progressive ossification in soft tissues. However, the specific cellular mechanisms are unclear.

Alternative splicing regulates mouse embryonic stem cell pluripotency and differentiation.

Two major goals of regenerative medicine are to reproducibly transform adult somatic cells into a pluripotent state and to control their differentiation into specific cell fates. Progress toward these goals would be greatly helped by obtaining a complete picture of the RNA isoforms produced by these cells due to alternative splicing (AS) and alternative promoter selection (APS). To investigate the roles of AS and APS, reciprocal exon-exon junctions were interrogated on a genome-wide scale in differentiating mouse embryonic stem (ES) cells with a prototype Affymetrix microarray.

Labeling human embryonic stem cell-derived cardiomyocytes with indocyanine green for noninvasive tracking with optical imaging: an FDA-compatible alternative to firefly luciferase.

Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) have demonstrated the ability to improve myocardial function following transplantation into an ischemic heart; however, the functional benefits are transient possibly due to poor cell retention. A diagnostic technique that could visualize transplanted hESC-CMs could help to optimize stem cell delivery techniques. Thus, the purpose of this study was to develop a labeling technique for hESCs and hESC-CMs with the FDA-approved contrast agent indocyanine green (ICG) for optical imaging (OI).

Biochemical activity of reactive oxygen species scavengers do not predict retinal ganglion cell survival.

Purpose: Retinal ganglion cells (RGCs) die as a result of axonal injury in a variety of optic neuropathies, including glaucoma. Reactive oxygen species (ROS) act as intracellular signaling molecules and initiate apoptosis in nerve growth factor-deprived sympathetic neurons and axotomized RGCs. Determination of the role of specific ROS relies on the use of small molecule or protein scavengers with various degrees of specificity.

Synthesis and characterization of a novel class of reducing agents that are highly neuroprotective for retinal ganglion cells.

Retinal ganglion cells (RGCs) undergo apoptosis after axonal injury, in part regulated by an intracellular superoxide anion burst, for which the target(s) are unknown. Shifting the RGC redox state towards reduction and preventing sulfhydryl oxidation is neuroprotective in vitro and in vivo, implying that one or more sulfhydryls on one or more critical proteins may be involved. We synthesized novel borane-protected analogues of the reductant tris(2-carboxyethyl)phosphine (TCEP) with the intent of increasing cell permeability and improving chemical stability, and tested their ability to increase RGC survival in vitro.

Retinal ganglion cell axotomy induces an increase in intracellular superoxide anion.

Purpose: Retinal ganglion cells (RGCs) undergo apoptosis after axonal injury. The time course of cell death is variable and depends in part on the degree of injury sustained. Decreasing reactive oxygen species (ROS) levels or shifting the redox state to reduction promotes the survival of RGCs in tissue culture after axotomy.

Kinase-dependent differentiation of a retinal ganglion cell precursor.

Purpose: Cell lines are frequently used to elucidate mechanisms of disease pathophysiology. Yet extrapolation of results with cell lines to neurodegenerative disorders is difficult because they are mitotic and usually have other non-neuronal properties. The RGC-5 cell line has many features of retinal ganglion cells (RGCs).

Neuroprotective effect of sulfhydryl reduction in a rat optic nerve crush model.

Purpose: The signaling of retinal ganglion cell (RGC) death after axotomy is partly dependent on the generation of reactive oxygen species. Shifting the RGC redox state toward reduction is protective in a dissociated mixed retinal culture model of axotomy. The hypothesis for the current study was that tris(2-carboxyethyl)phosphine (TCEP), a sulfhydryl reductant, would protect RGCs in a rat optic nerve crush model of axotomy.