Purpose of ReviewIntestinal epithelial cells show remarkable plasticity in regenerating the epithelium following radiation injury. In this review, we explore the regenerative capacity and mechanisms of various populations of intestinal stem cells (ISCs) in response to ionizing radiation.Recent FindingsIonizing radiation targets mitotic cells that include “active” ISCs and progenitor cells. Lineage-tracing experiments showed that several different cell types identified by a single or combination of markers are capable of regenerating the epithelium, confirming that ISCs exhibit a high degree of plasticity. However, the identities of the contributing cells marked by various markers require further validation.SummaryFollowing radiation injury, quiescent and/or radioresistant cells become active stem cells to regenerate the epithelium. Looking forward, understanding the mechanisms by which ISCs govern tissue regeneration is crucial to determine therapeutic approaches to promote intestinal epithelial regeneration following injury.

Specificity proteins (SPs) and Krüppel-like factors (KLFs) belong to the family of transcription factors that contain conserved zinc finger domains involved in binding to target DNA sequences. Many of these proteins are expressed in different tissues and have distinct tissue-specific activities and functions. Studies demonstrate that SPs and KLFs regulate not only physiological processes such as growth, development, differentiation, proliferation, and embryogenesis, but pathogenesis of many diseases, including cancer and inflammatory disorders. Consistently, these proteins have been shown to regulate normal functions and pathobiology in the digestive system. We review recent findings on the tissue- and organ-specific functions of SPs and KLFs in the digestive system including the oral cavity, esophagus, stomach, small and large intestines, pancreas, and liver. We provide a list of agents under development to target these proteins.

SummaryIn response to ionizing radiation-induced injury, the normally quiescent intestinal stem cells marked by BMI1 participate in the regenerative response. Previously, we established a protective role for Krüppel-like factor 4 (KLF4) in the intestinal epithelium where it reduces senescence, apoptosis, and crypt atrophy following γ-radiation-induced gut injury. We also described a pro-proliferative function for KLF4 during the regenerative phase post irradiation. In the current study, using a mouse model in which Klf4 is deleted from quiescent BMI1+ intestinal stem cells, we observed increased proliferation from the BMI1+ lineage during homeostasis. In contrast, following irradiation, Bmi1-specific Klf4 deletion leads to decreased expansion of the BMI1+ lineage due to a combination of reduced proliferation and increased apoptosis. Our results support a critical role for KLF4 in modulating BMI1+ intestinal stem cell fate in both homeostasis and the regenerative response to radiation injury.

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Lgr5 þ ISCs lacking KLF5 proliferate faster than control ISCs but fail to self-renew, resulting in a depleted ISC compartment. Transcriptome analysis revealed that Klf5-null Lgr5 þ cells lose ISC identity and prematurely differentiate. Following irradiation injury, which depletes Lgr5 þ ISCs, reserve Klf5-null progenitor cells fail to dedifferentiate and regenerate the epithelium. Absence of KLF5 inactivates numerous selected enhancer elements and direct transcriptional targets including canonical WNT-and NOTCHresponsive genes. Analysis of human intestinal tissues showed increased levels of KLF5 in the regenerating epithelium as compared to those of healthy controls. CONCLUSION: We conclude that ISC self-renewal, lineage specification, and precursor dedifferentiation require KLF5, by its ability to regulate epigenetic and transcriptional activities of ISC-specific gene sets. These findings have the potential for modulating ISC functions by targeting KLF5 in the intestinal epithelium.

A new and simple cantilever type Pb(Zr, Ti)O3 [PZT] microactuator was fabricated by adopting RuO2. The RuO2 has reasonably good conductivity and stiffness and it can replace the double layer of electrode and supporting layer to a single layer in a cantilever beam. The RuO2, PZT and Al thin films were deposited on the Si substrate. The patterning of the Al was carried out by a lithography process and etched with a chemical wet etchant. The etching of PZT and RuO2 were performed by a reactive ion etching system. The Si was etched isotropically to form a cantilever beam. The fabricated cantilever beam consists of Al, PZT and RuO2, and the thicknesses of the films are 0.40, 0.25 and 0.70 µm, respectively. The beams were from 140 µm to 275 µm in length and all of them were 60 µm wide. Driving tilt angles of the cantilever beams were almost proportional to the applied voltages.

The adult intestinal epithelium has a remarkable capacity for renewal that is driven by the activity of stem cells located in the intestinal crypts. Until now two major types of the intestinal stem cells have been identified: (I) actively proliferating intestinal stem cells (aISC), expressing Lgr5, that reside at the bottom of the crypts and are fastcycling and sensitive to injury, e.g., irradiation (1), and (II) quiescent or reserve intestinal stem cells (qISC or rISC), characterized by expression of Bmi1, mTert, and Hopx, that reside at +4 position of the crypt and are slow-cycling and have been shown to facilitate the regeneration of the intestinal epithelium upon injury.Recent studies have shown that despite divergent characteristics, these two populations of intestinal stem cells display a significant degree of plasticity between them. To further add to the versatile functions of intestinal crypt cells in maintaining epithelial homeostasis, Tetteh et al. recently reported that the enterocyte precursors have the ability to dedifferentiate into stem cells upon the ablation of the Lgr5 + expressing aISCs (2). They showed that the enterocyte differentiation marker alkaline phosphatase intestinal (Alpi) gene is highly expressed not only in the mature enterocytes but in the +6 and +7 positions and coincided with the KI67 proliferative marker in the transit amplifying (TA) zone of the crypts. This finding was critical in identifying

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