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In the developing neural retina (NR), multipotent stem cells within the ciliary margin (CM) contribute to de novo retinal tissue growth. We recently reported the ability of human embryonic stem cells (hESCs) to self-organize stratified NR using a three-dimensional culture technique. Here we report the emergence of CM-like stem cell niches within human retinal tissue. First, we developed a culture method for selective NR differentiation by timed BMP4 treatment. We then found that inhibiting GSK3 and FGFR induced the transition from NR tissue to retinal pigment epithelium (RPE), and that removing this inhibition facilitated the reversion of this RPE-like tissue back to the NR fate. This step-wise induction-reversal method generated tissue aggregates with RPE at the margin of central-peripherally polarized NR. We demonstrate that the NR–RPE boundary tissue further self-organizes a niche for CM stem cells that functions to expand the NR peripherally by de novo progenitor generation. The ciliary margin of the eye functions as a source of multipotent progenitor cells in certain organisms but whether it plays this role in humans has not been easy to study. Here the authors culture human embryonic stem cells that self-organize into retinal tissue, and show that ciliary margin-like growth zones emerge from the developing human retinal tissue and contain stem cell niches.

Anterior pituitary is critical for endocrine systems. Its hormonal responses to positive and negative regulators are indispensable for homeostasis. For this reason, generating human anterior pituitary tissue that retains regulatory hormonal control in vitro is an important step for the development of cell transplantation therapy for pituitary diseases. Here we achieve this by recapitulating mouse pituitary development using human embryonic stem cells. We find that anterior pituitary self-forms in vitro following the co-induction of hypothalamic and oral ectoderm. The juxtaposition of these tissues facilitated the formation of pituitary placode, which subsequently differentiated into pituitary hormone-producing cells. They responded normally to both releasing and feedback signals. In addition, after transplantation into hypopituitary mice, the in vitro -generated corticotrophs rescued physical activity levels and survival of the hosts. Thus, we report a useful methodology for the production of regulator-responsive human pituitary tissue that may benefit future studies in regenerative medicine. It is difficult to generate functional human anterior pituitary tissues in vitro . Here, Ozone et al. generate human anterior pituitary from embryonic stem cells by recapitulating in vivo development, and demonstrate this tissue secretes hormones and rescues hypopituitarism when grafted into mice.

For pituitary regenerative medicine, the creation of a hypophyseal model in monkeys is necessary to conduct future preclinical studies; however, previous studies reported that hypophysectomy in monkeys is not always safe or satisfactory. This study aimed to create a hypophyseal dysfunction model in a cynomolgus monkey using a safer surgical technique and establish the protocol of pituitary hormone replacement therapy for this model. Surgical resection of the pituitary gland of a 7.8-year-old healthy adult cynomolgus male monkey weighing 5.45 kg was performed to create a hypophyseal dysfunction model for future regenerative studies. Endoscopic transoral transsphenoidal surgery was used to perform hypophysectomy under navigation support. These procedures were useful for confirming total removal of the pituitary gland without additional bone removal and preventing complications such as cerebrospinal fluid leakage. Total removal was confirmed by pathological examination and computed tomography. Hypopituitarism was verified with endocrinological examinations including stimulation tests. Postoperatively, the monkey’s general condition of hypopituitarism was treated with hormone replacement therapy, resulting in long-term survival. The success of a minimally invasive and safe surgical method and long-term survival indicate the creation of a hypophyseal dysfunction model in a cynomolgus monkey; hence, this protocol can be employed in the future.

Arginine-vasopressin (AVP) neurons exist in the hypothalamus, a major region of the diencephalon, and play an essential role in water balance. Here, we established the differentiation method for AVP-secreting neurons from human embryonic stem cells (hESCs) by recapitulating in vitro the in vivo embryonic developmental processes of AVP neurons. At first, the differentiation efficiency was improved. That was achieved through the optimization of the culture condition for obtaining dorsal hypothalamic progenitors. Secondly, the induced AVP neurons were identified by immunohistochemistry and these neurons secreted AVP after potassium chloride stimulation. Additionally, other hypothalamic neuropeptides were also detected, such as oxytocin, corticotropin-releasing hormone, thyrotropin-releasing hormone, pro-opiomelanocortin, agouti-related peptide, orexin, and melanin-concentrating hormone. This is the first report describing the generation of secretory AVP neurons derived from hESCs. This method will be applicable to research using disease models and, potentially, for regenerative medicine of the hypothalamus.

Abstract Context Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) have the potential to improve native kidney function. Objective This work aimed to elucidate the possible protective effects of GLP-1 RAs on kidney graft function after successful kidney transplantation (KTX). Methods This retrospective cohort study included all KTX recipients (KTRs) at our facility with type 2 diabetes who were followed up from 1 month post-transplantation for 24 months or longer as of December 31, 2020. We investigated associations between the use of GLP-1 RAs and other antidiabetic medications (non–GLP-1 RAs) and the risk of sustained estimated glomerular filtration rate (eGFR) reduction (40% reduction compared with baseline for 4 months) for KTRs with type 2 diabetes. We calculated the propensity score of initiating GLP-1 RAs compared with that of initiating non–GLP-1 RAs as a function of baseline covariates using logistic regression. The inverse probability of the treatment-weighted odds ratio was estimated to control for baseline confounding variables. Sodium-glucose cotransporter 2 inhibitor use was a competing event. The primary outcome was sustained eGFR reduction of at least 40% from baseline for 4 months post-transplantation. Results Seventy-three patients were GLP-1 RA users and 73 were non–GLP-1 RA users. Six patients and 1 patient in the non–GLP-1 RA and GLP-1 RA groups had sustained eGFR reduction. GLP-1 RA use after KTX was associated with a lower risk of sustained eGFR reduction. Conclusion GLP-1 RAs resulted in lower eGFR reduction compared with non–GLP-1 RAs and may contribute to better kidney graft survival after KTX.

Introduction Fibrous dysplasia/McCune-Albright Syndrome (FD/MAS) is a rare multi-endocrine disorder with bone abnormalities called polyostonic fibrous dysplasia, presumably related to fibrous growth factor 23 (FGF23). We present a case of a patient with FD/MAS who successfully underwent spinal fusion surgery after efficacious anti-FGF23 treatment using its monoclonal antibody (burosumab). Clinical Case A late teenage boy, clinically diagnosed with FD/MAS, was referred to our hospital for possible treatment of burosumab, because he desperately needed promising medical intervention for bisphosphonate-resistant severe polyostonic fibrous dysplasia with enormously high turnover bone disease. On presentation, he had severe scoliosis (>80 degree-thoracic spine curve) with mild hypophosphatemia (2.5 mg/dL), low 25-hydroxyvitamin D (7.3 ng/mL), normal corrected calcium (9.6mg/dL) and high intact PTH (95.7 pg/mL). His FGF23 level was 90.4pg/mL, which was inappropriately high. He had a history of previous bilateral hip fractures with partially removed Café au macules on the back. Baseline laboratory findings revealed no remarkable signs of endocrinopathies, whereas serum bone markers were remarkably high (tartrate-resistant acid phosphatase 5b, >1500 mU/dL; procollagen type 1 N-propeptide, >1200 ng/mL, alkaline phosphatase, 2638 U/L). He was started on monthly 50mg of burosumab therapy subcutaneously. Interestingly enough, his alkaline phosphatase levels gradually decreased down to 1619 U/L at month 6 post-anti-FGF23 treatment. Subsequent spine fusion surgery was successfully underwent with his thoracic curve corrected by instrumentation. Discussion This is, to our knowledge, the first case with FD/MAS, who was given monthly burosumab, followed by orthopedic spinal instrumentation to straighten the spine curve. Burosumab treatment for FD/MAS may enhance bone flexibility by blocking abnormal FGF23-related signaling, enabling safer approach to promising orthopedic surgeries. Presentation: No date and time listed

Diabetic kidney disease (DKD), a devastating complication of diabetes, is one of the leading causes of end stage kidney disease (ESKD). Kidney transplantation provides superior outcomes for ESKD patients with type 2 diabetes, giving opportunities to be free from dialysis, but needs lifetime immunosuppressive medications to avoid graft kidney rejection. Post-transplant hyperglycemia, however, remains to be unsolved, because immunosuppressive agents, including glucocorticoids and calcineurin inhibitors, may result in impaired insulin secretion and sensitivity. Safe and promising anti-diabetic strategy is long-awaited among kidney transplant recipients (KTRs) with type 2 diabetes. Enormous evidence has accumulated that Glucagon-like peptide 1 (GLP-1) receptor agonists have potential to maintain kidney function as well as improve glucose tolerance in patients with DKD. The present study was designed to elucidate the association between GLP-1 receptor agonist use and better graft kidney function in KTRs with type 2 diabetes. Among KTRs with type 2 diabetes between 2012 and 2019, 73 with GLP-1 receptor agonist use and 73 without GLP-1 receptor use were identified in our center. After propensity matching, 50 KTRs were newly initiated with GLP-1 receptor agonist use or other antidiabetic medications. Baseline characteristics were well-balanced in the 2 groups. KTRs with GLP-1 receptor agonist use had greater kidney function 12 months after initiation of GLP-1 receptor agonists, compared to their counterpart KTRs without GLP-1 receptor agonists, according to estimated glomerular filtration ratio (p=0.01). Interestingly, transient decrease of body mass index was observed in KTRs with GLP-1 receptor agonist use during the 12 months. All GLP-1 receptor agonist-initiated KTRs were followed up through December 31, 2019. In conclusion, GLP-1 receptor agonist treatment was associated with better graft kidney function in KTRs with type 2 diabetes. Pharmacological GLP-1 receptor activation showed favorable tolerability and may alleviate graft kidney damage in KTRs with type 2 diabetes.