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Cisplatin-induced acute kidney injury (CIAKI) is a common complication in patients receiving cisplatin-based chemotherapy. But the effective therapies for CIAKI are not available. Retinoic acid (RA), the main derivative of vitamin A, has the potential to reduce inflammation and fibrosis in renal injury. However, the effect and mechanism of RA on CIAKI are still unclear. The aim of this study is to investigate whether RA can alleviate CIAKI through activation of autophagy. In this study, we evaluated the effect of RA, RA's effect on autophagy and apoptosis after cisplatin-induced injury on renal tubular epithelial cells (RTECs) by LDH assay, immunoblotting and TUNEL staining. Then we established Atg5flox/flox:Cagg-Cre mice in which Cagg-Cre is tamoxifen inducible, and Atg5 is conditional deleted after tamoxifen injection. The effect of RA and RA's effect on autophagy on CIAKI model were evaluated by biochemical assessment, hematoxylin and eosin (HE) staining, and immunoblotting in the control and autophagy deficient mice. In vitro , RA protected RTECs against cisplatin-induced injury, activated autophagy, and inhibited cisplatin-induced apoptosis. In vivo , RA attenuated cisplatin-induced tubular damage, shown by improved renal function, decreased renal cast formation, decreased NGAL expression, and activated autophagy in the control mice. Furthermore, the nephrotoxicity of cisplatin was aggravated, and the protective effect of RA was attenuated in autophagy deficient mice, indicating that RA works in an autophagy-dependent manner on CIAKI. RA activates autophagy and alleviates CIAKI in vivo and in vitro.Thus RA may be a renoprotective adjuvant for cisplatin-based chemotherapy. [ABSTRACT FROM AUTHOR]

The brainstem is a posterior region of the brain, composed of three parts, midbrain, pons, and medulla oblongata. It is critical in controlling heartbeat, blood pressure, and respiration, all of which are life-sustaining functions, and therefore, damages to or disorders of the brainstem can be lethal. Brain organoids derived from human pluripotent stem cells (hPSCs) recapitulate the course of human brain development and are expected to be useful for medical research on central nervous system disorders. However, existing organoid models are limited in the extent hPSCs recapitulate human brain development and hence are not able to fully elucidate the diseases affecting various components of the brain such as brainstem. Here, we developed a method to generate human brainstem organoids (hBSOs), containing midbrain/hindbrain progenitors, noradrenergic and cholinergic neurons, dopaminergic neurons, and neural crest lineage cells. Single-cell RNA sequence (scRNA-seq) analysis, together with evidence from proteomics and electrophysiology, revealed that the cellular population in these organoids was similar to that of the human brainstem, which raises the possibility of making use of hBSOs in investigating central nervous system disorders affecting brainstem and in efficient drug screenings. [ABSTRACT FROM AUTHOR]

Three-dimensional (3D) organoid models derived from human pluripotent stem cells provide a platform for studying human development and understanding disease mechanisms. Most studies that examine biallelic inactivation of the cell cycle regulator Retinoblastoma 1 (RB1) and the link to retinoblastoma is in mice, however, less is known regarding the pathophysiological role of RB1 during human retinal development. To study the role of RB1 in early human retinal development and tumor formation, we generated retinal organoids from CRISPR/Cas9-derived RB1-null human embryonic stem cells (hESCs). We showed that RB is abundantly expressed in retinal progenitor cells in retinal organoids and loss of RB1 promotes S-phase entry. Furthermore, loss of RB1 resulted in widespread apoptosis and reduced the number of photoreceptor, ganglion, and bipolar cells. Interestingly, RB1 mutation in retinal organoids did not result in retinoblastoma formation in vitro or in the vitreous body of NOD/SCID immunodeficient mice. Together, our work identifies a crucial function for RB1 in human retinal development and suggests that RB1 deletion alone is not sufficient for tumor development, at least in human retinal organoids. A model of the role of RB1 during human retinal development. In wild-type cells, RB1 regulates entry into S-phase. While RB1 mutation in retinal organoids did not result in retinoblastoma formation, either in vitro or when injected into vitreous body of NOD/SCID mice, loss of RB1 promotes an accumulation of cells in S-phase, causes widespread apoptosis, and reduces the number of photoreceptor, ganglion and bipolar cells. Image 1 • RB expression is highest in progenitor cells and downregulated during maturation stages. • RB1 is required for S-phase entry and cell survival in retinal organoids. • RB1 is necessary for photoreceptor, ganglion and bipolar cell differentiation. • Loss of RB1 is not sufficient for retinoblastoma formation in retinal organoids. [ABSTRACT FROM AUTHOR]

Introduction: The reconstruction of extensive three-dimensional defects in the extremities is a difficult challenge. Many attempts have been made to reconstruct such defects using the chimeric flap concept, enabling flaps with larger surface areas to be used while maintaining economical tissue use. The anterolateral thigh (ALT) chimeric flap is one of the most useful tools for the reconstruction of complex three-dimensional defects in the extremities.Methods: From January 2010 to March 2012, Twenty-two patients underwent extremity reconstruction using chimeric ALT perforator flaps, which consists of a skin component on its isolated perforator and a portion of the fascia and muscle flaps on the same pedicle from the descending branch of the lateral circumflex femoral artery (LCFA). The defects were in either a lower (n = 10) or an upper extremity (n = 12). The area of the soft tissue defects ranged from 43 × 35 cm to 19 × 9 cm (mean, 25 × 18 cm), containing extensive, irregular, ring-like soft tissue defects or degloving injuries.Results: The mean dimension of skin flap was 19.8 × 11.2 cm. The mean dimension of fascia flap was 8.9 × 7.1 cm. The mean dimension of muscle flap was 11.1 × 7.5 cm. No total flap loss occurred. One patient presented with venous thrombosis, and re-anastomosis and vein grafting were performed. Two cases exhibiting partial skin graft loss at the site at which the fascia flap was inset were treated via secondary skin grafts. During a follow-up period of 18 months-30 months, patients were satisfied with the functional and aesthetic outcome. No serious donor-site complications occurred.Discussion: Chimeric anterolateral thigh perforator flap can be one of the best choice for reconstruction of complex soft-tissue defects in the extremities.Conclusions: The various tissue components and maximal freedom offered by chimeric tissue flaps associated with the same descending branch of the LCFA provide versatile coverage of large, complex, and irregular soft-tissue defects in the extremities. [ABSTRACT FROM AUTHOR]

Growing human organs in animals sounds like something from the realm of science fiction, but it may one day become a reality through a technique known as interspecies blastocyst complementation. This technique, which was originally developed to study gene function in development, involves injecting donor pluripotent stem cells into an organogenesis-disabled host embryo, allowing the donor cells to compensate for missing organs or tissues. Although interspecies blastocyst complementation has been achieved between closely related species, such as mice and rats, the situation becomes much more difficult for species that are far apart on the evolutionary tree. This is presumably because of layers of xenogeneic barriers that are a result of divergent evolution. In this Review, we discuss the current status of blastocyst complementation approaches and, in light of recent progress, elaborate on the keys to success for interspecies blastocyst complementation and organ generation., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

Dynamic pluripotent stem cell (PSC) states are in vitro adaptations of pluripotency continuum in vivo. Previous studies have generated a number of PSCs with distinct properties. To date, however, no known PSCs have demonstrated dual competency for chimera formation and direct responsiveness to primordial germ cell (PGC) specification, a unique functional feature of formative pluripotency. Here, by modulating fibroblast growth factor (FGF), transforming growth factor β (TGF-β), and WNT pathways, we derived PSCs from mice, horses, and humans (designated as XPSCs) that are permissive for direct PGC-like cell induction in vitro and are capable of contributing to intra- or inter-species chimeras in vivo. XPSCs represent a pluripotency state between naive and primed pluripotency and harbor molecular, cellular, and phenotypic features characteristic of formative pluripotency. XPSCs open new avenues for studying mammalian pluripotency and dissecting the molecular mechanisms governing PGC specification. Our method may be broadly applicable for the derivation of analogous stem cells from other mammalian species., Competing Interests: Declaration of Interests L.Y. and J.W. are inventors on a patent application arising from this work. The other authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)