Enterogenesis in a clinically feasible model of mechanical small-bowel lengthening

Spencer, Ariel U.; Sun, Xiaoyi; Elsawaf, Mohamed; Haxhija, Emir Q.; Brei, Diann; Luntz, Jonathan; Yang, Hua; Teitelbaum, Daniel H.

doi:10.1016/j.surg.2006.03.005

Cited by 46 publications

(45 citation statements)

References 35 publications

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“…However, Teitelbaum and co-workers (14) has previously demonstrated that stretching pig intestine in vivo is associated with a increased cell proliferation while maintaining the function of the intestinal mucosa, whereas repetitive deformation of the anesthetized rat jejunum or colon activates tyrosine kinase signaling within the mucosa (75). Moreover, proliferation is decreased in murine intestinal mucosa distal to a partial small bowel obstruction, consistent with the concept that strain and pressure may be mitogenic for intestinal epithelial cells (76).…”

Section: Discussionsupporting

confidence: 62%

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Strain-induced Proliferation Requires the Phosphatidylinositol 3-Kinase/AKT/Glycogen Synthase Kinase Pathway

Gayer

Chaturvedi

Wang

et al. 2009

Journal of Biological Chemistry

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The intestinal epithelium is repetitively deformed by shear, peristalsis, and villous motility. Such repetitive deformation stimulates the proliferation of intestinal epithelial cells on collagen or laminin substrates via ERK, but the upstream mediators of this effect are poorly understood. We hypothesized that the phosphatidylinositol 3-kinase (PI3K)/AKT cascade mediates this mitogenic effect. PI3K, AKT, and glycogen synthase kinase-3␤ (GSK-3␤) were phosphorylated by 10 cycles/min strain at an average 10% deformation, and pharmacologic blockade of these molecules or reduction by small interfering RNA (siRNA) prevented the mitogenic effect of strain in Caco-2 or IEC-6 intestinal epithelial cells. Strain MAPK activation required PI3K but not AKT. AKT isoform-specific siRNA transfection demonstrated that AKT2 but not AKT1 is required for GSK-3␤ phosphorylation and the strain mitogenic effect. Furthermore, overexpression of AKT1 or an AKT chimera including the PH domain and hinge region of AKT2 and the catalytic domain and C-tail of AKT1 prevented strain activation of GSK-3␤, but overexpression of AKT2 or a chimera including the PH domain and hinge region of AKT1 and the catalytic domain and C-tail of AKT2 did not. These data delineate a role for PI3K, AKT2, and GSK-3␤ in the mitogenic effect of strain. PI3K is required for both ERK and AKT2 activation, whereas AKT2 is sequentially required for GSK-3␤. Furthermore, AKT2 specificity requires its catalytic domain and tail region. Manipulating this pathway may prevent mucosal atrophy and maintain the mucosal barrier in conditions such as ileus, sepsis, and prolonged fasting when peristalsis and villous motility are decreased and the mucosal barrier fails.

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Section: Discussionsupporting

confidence: 62%

“…Cyclic strain also stimulates proliferation in HCT 116 colon cancer cells (13) and differentiation of Caco-2 cells cultured on a collagen substrate (9). This phenomenon has also been observed in vivo (14). Thus, repetitive deformation may help to maintain the normal homeostasis of the gut mucosa under non-inflammatory conditions.…”

mentioning

confidence: 70%

Strain-induced Proliferation Requires the Phosphatidylinositol 3-Kinase/AKT/Glycogen Synthase Kinase Pathway

Gayer

Chaturvedi

Wang

et al. 2009

Journal of Biological Chemistry

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“…39 A critical consequence of SBS is loss of absorption area, so recent research has focused on increasing absorption area. 11,12,41,42 The use of growth factors may result in significant increase in bowel adaptation. 43 Using an implanted mechanical device in pigs, our laboratory demonstrated a far greater increase in adaptation than can be achieved with growth factors-nearly three-fold increase in small bowel length 12 In addition to lengthening of the bowel, epithelial cell FIG.…”

Section: Discussionmentioning

confidence: 99%

“…[9][10][11] Previously, we demonstrated a 2.7-fold increase in bowel length over 10 days using an implanted hydraulic piston device in a pig model. 12 Physiologic function was retained in the lengthened gut after reimplantation, including motility, epithelial barrier function, mucosal disaccharidase levels, and electrophysiologic measures. 13 Further, reimplantation of the bowel into normal intestinal continuity demonstrated preservation of lengthening.…”

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confidence: 99%

Distraction-Induced Intestinal Growth: The Role of Mechanotransduction Mechanisms in a Mouse Model of Short Bowel Syndrome

Sueyoshi

Ignatoski

Okawada

et al. 2013

Tissue Engineering Part A

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Novel strategies are needed to address the problem of patients with short bowel syndrome. We previously demonstrated a three-fold lengthening of pig bowel after 2 weeks of applied distractive forces, but we have not elucidated the mechanisms facilitating this growth. We used a mouse model of distraction-induced enterogenesis. High molecular weight polyethylene glycol (PEG) osmotically stretched an isolated small bowel segment (PEG-stretch). Significant increases in villus height and crypt depth and in intestinal epithelial cell length and numbers suggested epithelial remodeling in addition to proliferation during enterogenesis. LC-MS/ MS analysis showed a two-fold upregulation of a-actinin-1 and -4. We also demonstrated that p-focal adhesion kinase (FAK), FAK, a-actinin, and Rac1 were significantly upregulated and that F-actin was relocalized in PEGstretch versus controls. Blockade of the phosphotidyl inositol 3¢ kinase pathway failed to influence the increase in proliferation or decline in apoptosis after stretch, suggesting alternative signaling pathways are used, including MEK and P38MAPK, which were both upregulated during enterogenesis. Our data suggests that several known mechanotransduction pathways drive distraction-induced enterogenesis.

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“…The resultant intestine must function mechanically as well as biologically. Several reports have shown successful lengthening of intestine in both rats and pigs with preservation of the mechanical properties of intestinal smooth muscle as well as enzymatic and absorptive properties [11,[32][33][34]. Muscle contraction strength and rate of stretched rat jejunum were measured in organ baths with cholinergic stimulation [32].…”

Section: Challenges In Experimental Designmentioning

confidence: 99%

Mechanical Enterogenesis ‐ A Review

Stark¹,

Dunn²

2012

Journal of Healthcare Engineering

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Mechanical enterogenesis is a novel method of lengthening pre-existing intestine with distractive force. The application of mechanical force on small intestine aims to induce cellular proliferation and ultimately increase bowel length. This has been investigated primarily for the treatment of short bowel syndrome (SBS). Research has been ongoing for well over a decade in this arena and a multitude of advances have been made, both in the understanding of the biology behind force induced cellular proliferation and in the basic mechanics of force delivery systems. Important experimental models have been developed for studying this phenomenon and the collaboration of engineers and medical researchers has lead to the design of several devices that successfully lengthen small intestine. This has catapulted the field forward and there may soon be a device suitable for medical use in humans. This review analyses the past, present and future of mechanical enterogenesis.

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Enterogenesis in a clinically feasible model of mechanical small-bowel lengthening

Abstract: Background-Recent work indicates that mechanical force induces small-bowel growth, although methods reported do not have direct clinical application. We report a clinically feasible technique of enterogenesis and describe intestinal function in this model.

Cited by 46 publications

References 35 publications

Strain-induced Proliferation Requires the Phosphatidylinositol 3-Kinase/AKT/Glycogen Synthase Kinase Pathway

Strain-induced Proliferation Requires the Phosphatidylinositol 3-Kinase/AKT/Glycogen Synthase Kinase Pathway

Distraction-Induced Intestinal Growth: The Role of Mechanotransduction Mechanisms in a Mouse Model of Short Bowel Syndrome

Mechanical Enterogenesis ‐ A Review

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