Epidermal Stem Cells in Skin Wound Healing.

Significance: Skin serves as a protective barrier for mammals. Epidermal stem cells are responsible for maintaining skin homeostasis. When cutaneous injuries occur, skin homeostasis and integrity are damaged, leading to dire consequences such as acute, chronic, or infected wounds. Skin wound healing is an intrinsic self-saving chain reaction, which is crucial to facilitating the replacement of damaged or lost tissue. Recent Advances: An immense amount of research has uncovered the underlying mechanisms behind the complex and highly regulated wound healing process. In this review, we will dissect the biological process of adult skin wound healing and emphasize the importance of epidermal stem cells during the wound healing. Critical Issues: We will comprehensively discuss the current clinical practices used on patients with cutaneous wounds, including both traditional skin grafting procedures and advanced grafting techniques with cultured skin stem cells. The majority of these leading techniques still retain some deficiencies during clinical use. Moreover, the regeneration of skin appendages after severe injuries remains a challenge in treatment. Future Directions: Understanding epidermal stem cells and their essential functions during skin wound healing are fundamental components behind the development of clinical treatment on patients with cutaneous wounds. It is important to improve the current standard of care and to develop novel techniques improving patient outcomes and long-term rehabilitation, which should be the goals of future endeavors in the field of skin wound healing.

Erratum: ACF7 regulates inflammatory colitis and intestinal wound response by orchestrating tight junction dynamics.

This corrects the article DOI: 10.1038/ncomms15375.

Spectraplakin family proteins - cytoskeletal crosslinkers with versatile roles.

The different cytoskeletal networks in a cell are responsible for many fundamental cellular processes. Current studies have shown that spectraplakins, cytoskeletal crosslinkers that combine features of both the spectrin and plakin families of crosslinkers, have a critical role in integrating these different cytoskeletal networks. Spectraplakin genes give rise to a variety of isoforms that have distinct functions. Importantly, all spectraplakin isoforms are uniquely able to associate with all three elements of the cytoskeleton, namely, F-actin, microtubules and intermediate filaments. In this Review, we will highlight recent studies that have unraveled their function in a wide range of different processes, from regulating cell adhesion in skin keratinocytes to neuronal cell migration. Taken together, this work has revealed a diverse and indispensable role for orchestrating the function of different cytoskeletal elements in vivo.

ACF7 regulates inflammatory colitis and intestinal wound response by orchestrating tight junction dynamics.

In the intestinal epithelium, the aberrant regulation of cell/cell junctions leads to intestinal barrier defects, which may promote the onset and enhance the severity of inflammatory bowel disease (IBD). However, it remains unclear how the coordinated behaviour of cytoskeletal network may contribute to cell junctional dynamics. In this report, we identified ACF7, a crosslinker of microtubules and F-actin, as an essential player in this process. Loss of ACF7 leads to aberrant microtubule organization, tight junction stabilization and impaired wound closure in vitro. With the mouse genetics approach, we show that ablation of ACF7 inhibits intestinal wound healing and greatly increases susceptibility to experimental colitis in mice. ACF7 level is also correlated with development and progression of ulcerative colitis (UC) in human patients. Together, our results reveal an important molecular mechanism whereby coordinated cytoskeletal dynamics contributes to cell adhesion regulation during intestinal wound repair and the development of IBD.

Seminal Plasma Promotes Lesion Development in a Xenograft Model of Endometriosis.

The factors that predispose one-tenth of reproductive-aged women to endometriosis are poorly understood. We determined that genetic deficiency in transforming growth factor ß1 impairs endometriosis-like lesion growth in mice. Given that seminal plasma is an abundant source of transforming growth factor ß, we evaluated the effect of exposure to seminal plasma on the growth of endometrial lesions. Human endometrial explants were exposed to seminal plasma or to control medium before transfer to Prkdc(scid)-mutant (severe combined immunodeficient) mice. Xenografts exposed to seminal plasma showed an eightfold increase in volume and a 4.3-fold increase in weight after 14 days. These increases were associated with increased proliferation of endometrial epithelial cells and enhanced survival and proliferation of human stromal cells compared with those in control lesions, in which human stromal cell persistence was negligible. Although the distribution of macrophages was altered, their number and activation status did not change in response to seminal plasma. Seminal plasma stimulated the production of a variety of cytokines in endometrial tissue, including growth-regulated oncogene, granulocyte macrophage colony-stimulating factor, and IL-1ß. These data suggest that seminal plasma enhances the formation of endometriosis-like lesion via a direct effect on endometrial cell survival and proliferation, rather than via macrophage-mediated mechanisms. These findings raise the possibility that endometrial exposure to seminal plasma could contribute to endometriotic disease progression in women.

Maternal insulin-like growth factor 1 and 2 differentially affect the renin-angiotensin system during pregnancy in the guinea pig.

OBJECTIVE: Insulin-like growth factors (IGFs) are known to interact with the renin-angiotensin system (RAS). We previously demonstrated that administration of IGF1 to guinea pigs in early to mid pregnancy promotes placental function and fetal growth in mid to late gestation. Early administration of IGF2 had sustained, but not acute, effects on these parameters and also on placental structural differentiation. Here, we aimed to determine whether the IGFs interact with the placental RAS in early to mid gestation to modulate placental development and increase fetal growth and survival, and if IGF2 binding the IGF2R is implicated in the sustained effects of IGF2 treatment. DESIGN: At day 20 of pregnancy, guinea pigs were infused with 1m g/kg/day of IGF1, IGF2, (Leu27)IGF2 or vehicle for 18days and sacrificed on either day 62 (late pregnancy) or during the infusion period on day 35 (early-mid pregnancy). Placental structure at day 35 was analyzed using morphometric technique and expression of RAS genes in the placenta and placental and plasma renin activity were measured at both time points. RESULTS: Compared with vehicle at day 35 of gestation, IGF1 infusion reduced the total midsagittal cross-sectional area of the placenta (-17%, p = 0.02) and the labyrinth area (-22%, p = 0.014) but did not alter the labyrinth volume nor labyrinth:interlobium ratios. IGF2 treatment did not affect placental structure. IGF1 did not alter placental mRNA for any of the RAS genes quantified at day 35 (AGTR1, ACE, AGT, TGFB1) but increased TGFB1 expression by more than 16-fold (p = 0.005) at day 62. IGF2 increased placental expression of AGTR1 (+88%, p = 0.03) and decreased AGT (-73%, p = 0.01) compared with the vehicle-treated group at day 35, and both IGF2 and (Leu27)IGF2 increased expression of TGFB1 at day 62 by 9-fold (p = 0.016) and 6-fold (p = 0.019) respectively. Both IGFs increased the ratio of active:total placental renin protein (+22% p = 0.026 p = 0.038) compared to vehicle compared to vehicle at day 35 but not 62. At day 62, IGF2-treated mothers showed a marked increase in total plasma renin (+495%) and active renin (+359%) compared to vehicle but decreased the ratio of active to total renin by 41% (p = 0.042). (Leu27)IGF2-treated animals had higher levels of placental active renin (+73%, p = 0.001) and total renin (+71%, p = 0.001) compared with the vehicle control. CONCLUSIONS: The data obtained in the current study suggest the potential for alternate roles for the induction of the RAS after IGF treatment. IGF1 and 2 treatments increase the activation of prorenin to renin in the placenta, possibly due to increased protease activity. In addition, IGF2 treatment in early pregnancy may enhance the maternal adaptation to pregnancy through stimulation of renin in the kidney. The sustained effects on placental differentiation and function after IGF2 treatment suggest therapeutic potential for exogenous administration of IGFs in improving pregnancy outcomes.

Photosystem I on graphene as a highly transparent, photoactive electrode.

We report the fabrication of a hybrid light-harvesting electrode consisting of photosystem I (PSI) proteins extracted from spinach and adsorbed as a monolayer onto electrically contacted, large-area graphene. The transparency of graphene supports the choice of an opaque mediator at elevated concentrations. For example, we report a photocurrent of 550 nA/cm(2) from a monolayer of PSI on graphene in the presence of 20 mM methylene blue, which yields an opaque blue solution. The PSI-modified graphene electrode has a total thickness of less than 10 nm and demonstrates photoactivity that is an order of magnitude larger than that for unmodified graphene, establishing the feasibility of conjoining these nanomaterials as potential constructs in next-generation photovoltaic devices.

Dried matrix on paper disks: the next generation DBS microsampling technique for managing the hematocrit effect in DBS analysis.

BACKGROUND: The hematocrit effect is a hurdle for successful introduction of the dried blood spot (DBS) in a regulated environment. Recently, attempts were taken to overcome the hematocrit effect by whole-cut DBS analysis. This paper presents the next-generation whole-cut DBS; dried matrix on paper disks (DMPD). RESULTS: DMPD eliminated the hematocrit effect and demonstrated better accuracy and precision than regular DBS with partial punching. Observed accuracy and precision were 6.0 and 2.3% for DMPD, respectively, and -10.4 and 17.1%, for DBS, respectively. CONCLUSION: The DMPD technique performed better than regular DBS by eliminating the hematocrit effect related blood volume bias. Although this effect was not observed with DMPD, a systematic error of 6.0% was detected and further technical development of DMPD could improve the performance.

Association of vascular endothelial growth factor +936 C/T single-nucleotide polymorphism with pregnancies complicated by small-for-gestational-age babies.

OBJECTIVES: To examine whether single-nucleotide polymorphisms (SNPs) in VEGFA (-2578 C/A and +936 C/T) associate with small-for-gestational-age (SGA) pregnancies and to identify their effects on first-trimester placental VEGFA expression. DESIGN: Multicenter prospective cohort study. SETTINGS: Adelaide, Australia, and Auckland, New Zealand. PARTICIPANTS: A total of 3234 nulliparous pregnant women, their partners, and their infants. MAIN OUTCOME MEASURES: The SNPs in the parent-infant trios and first-trimester placentae (n = 74) were genotyped. Placental VEGFA messenger RNA expression was determined by quantitative reverse transcription-polymerase chain reaction. Small for gestational age was defined as a birth weight less than the 10th customized birth weight percentile adjusted for maternal height, weight, parity, and ethnicity and for gestational age at delivery and infant sex. Uterine and umbilical artery Doppler was performed at 20 weeks' gestation, and resistance indices greater than the 90th percentile were considered abnormal. RESULTS: Of 2123 pregnancies, 1176 (55.4%) were uncomplicated and 216 (10.2%) had SGA infants. Neonatal VEGFA +936 C/T SNP associates with SGA (adjusted odds ratio [aOR], 1.6; 95% CI, 1.0-2.3), SGA with abnormal Doppler findings (aOR, 3.5; 95% CI, 1.8-7.1), lower birth weight (P = .006), customized birth weight percentile (P = .049), and abnormal uterine artery Doppler findings (OR, 2.5; 95% CI, 1.2-5.4). Maternal VEGFA +936 C/T associates with abnormal umbilical artery Doppler findings (OR, 1.5; 95% CI, 1.1-2.2). VEGFA +936 CT+TT first-trimester placentae have 36% lower VEGFA messenger RNA expression compared with CC (P = .045). CONCLUSION: Neonatal VEGFA +936 C/T associates with SGA, and the association is stronger for SGA with abnormal uterine or umbilical artery Doppler findings. The SNP also associates with reduced first-trimester placental VEGFA expression, suggesting that it may have a role in the pathogenesis of SGA. Trial Registration clinicaltrials.gov Identifier: ACTRN12607000551493.