The embryonic chick is able to regenerate the retina after it has been removed. We have previously shown that proliferating stem/progenitor cells present in the ciliary body/ciliary marginal zone (CB/CMZ) of the chick eye are responsible for regeneration, which can be induced by ectopic fibroblast growth factor-2 (

We identified a mechanism whereby retina regeneration in the embryonic chick can be induced by the contribution of stem/ progenitor cells. We show that bone morphogenetic protein (BMP) signaling is sufficient and necessary to induce retina regeneration and that its action can be divided into two phases. By 3 days after postretinectomy (d PR), the BMP pathway directs proliferation and regeneration through the activation of Smad (canonical BMP pathway) and the up-regulation of FGF signaling by the MAPK pathway. By 7d PR, it induces apoptosis by activating p38 (a noncanonical BMP pathway) and down-regulating FGF signaling (by both MAPK and AKT pathways). Apoptosis at this later stage can be prevented, and BMP-induced regeneration can be further induced by inhibition of p38. These results unravel a mechanism for stem/ progenitor cell-mediated retina regeneration, where BMP activation establishes a cross-talk with the FGF pathway and selectively activates the canonical and noncanonical BMP pathways. Retina stem/progenitor cells exist in other species, including humans. Thus, our findings provide insights on how retinal stem cells can be activated for possible regenerative therapies.p38 ͉ FGF B one morphogenetic proteins (BMPs) are secreted signaling proteins that elicit their effect by binding to a heterodimer receptor complex composed of a BMP type I receptor (BMPRIA or BMPRIB) and a BMP type II receptor (BMPRII) (1). The BMP pathway can activate the canonical downstream effector, Smad, or a noncanonical downstream effector, transforming growth factor-␤-activated kinase (TAK1) (1). Several endogenous inhibitors, including noggin, chordin, follistatin, and gremlin, can regulate the ability of BMP to activate these pathways (2).In the developing retina, BMP2, BMP4, and BMP7, as well as the BMP receptors, are expressed in the chick (3) and mouse (4-6) and have been found to play a role in establishing the dorsal/ventral patterning of the retina. They also regulate the differentiation and survival of retinal neurons (7-11). Because of the BMP pathway's importance during retina development and in stem cell biology, we wanted to examine its role in inducing and regulating retina regeneration.A population of retinal stem cells is maintained after retinal development in the anterior margin of the eye in many vertebrates, including humans (12, 13). In most vertebrates, these retinal stem cells remain quiescent and do not respond to injury. However, cells in the anterior margin of the embryonic chick eye respond to injury during a limited time of retina development, providing an opportunity to study the induction process of these stem/progenitor cells (13-15).The embryonic chick has been shown to regenerate a complete retina in Ϸ7 days as long as a retinectomy is performed on or around embryonic day 4 (E4) and a source of FGF is added (14,16,17). In the presence of ectopic FGF2, regeneration takes place by transdifferentiation of the retinal pigmented epithelium (RPE) and the activation of retinal stem/progenitor cells (RS/ R...

We identified a mechanism whereby retina regeneration in the embryonic chick can be induced by the contribution of stem/ progenitor cells. We show that bone morphogenetic protein (BMP) signaling is sufficient and necessary to induce retina regeneration and that its action can be divided into two phases. By 3 days after postretinectomy (d PR), the BMP pathway directs proliferation and regeneration through the activation of Smad (canonical BMP pathway) and the up-regulation of FGF signaling by the MAPK pathway. By 7d PR, it induces apoptosis by activating p38 (a noncanonical BMP pathway) and down-regulating FGF signaling (by both MAPK and AKT pathways). Apoptosis at this later stage can be prevented, and BMP-induced regeneration can be further induced by inhibition of p38. These results unravel a mechanism for stem/ progenitor cell-mediated retina regeneration, where BMP activation establishes a cross-talk with the FGF pathway and selectively activates the canonical and noncanonical BMP pathways. Retina stem/progenitor cells exist in other species, including humans. Thus, our findings provide insights on how retinal stem cells can be activated for possible regenerative therapies.p38 ͉ FGF B one morphogenetic proteins (BMPs) are secreted signaling proteins that elicit their effect by binding to a heterodimer receptor complex composed of a BMP type I receptor (BMPRIA or BMPRIB) and a BMP type II receptor (BMPRII) (1). The BMP pathway can activate the canonical downstream effector, Smad, or a noncanonical downstream effector, transforming growth factor-␤-activated kinase (TAK1) (1). Several endogenous inhibitors, including noggin, chordin, follistatin, and gremlin, can regulate the ability of BMP to activate these pathways (2).In the developing retina, BMP2, BMP4, and BMP7, as well as the BMP receptors, are expressed in the chick (3) and mouse (4-6) and have been found to play a role in establishing the dorsal/ventral patterning of the retina. They also regulate the differentiation and survival of retinal neurons (7-11). Because of the BMP pathway's importance during retina development and in stem cell biology, we wanted to examine its role in inducing and regulating retina regeneration.A population of retinal stem cells is maintained after retinal development in the anterior margin of the eye in many vertebrates, including humans (12, 13). In most vertebrates, these retinal stem cells remain quiescent and do not respond to injury. However, cells in the anterior margin of the embryonic chick eye respond to injury during a limited time of retina development, providing an opportunity to study the induction process of these stem/progenitor cells (13-15).The embryonic chick has been shown to regenerate a complete retina in Ϸ7 days as long as a retinectomy is performed on or around embryonic day 4 (E4) and a source of FGF is added (14,16,17). In the presence of ectopic FGF2, regeneration takes place by transdifferentiation of the retinal pigmented epithelium (RPE) and the activation of retinal stem/progenitor cells (RS/ R...

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Background Timing of initiation of kidney-replacement therapy (KRT) in critically ill patients remains controversial. The Standard versus Accelerated Initiation of Renal-Replacement Therapy in Acute Kidney Injury (STARRT-AKI) trial compared two strategies of KRT initiation (accelerated versus standard) in critically ill patients with acute kidney injury and found neutral results for 90-day all-cause mortality. Probabilistic exploration of the trial endpoints may enable greater understanding of the trial findings. We aimed to perform a reanalysis using a Bayesian framework. Methods We performed a secondary analysis of all 2927 patients randomized in multi-national STARRT-AKI trial, performed at 168 centers in 15 countries. The primary endpoint, 90-day all-cause mortality, was evaluated using hierarchical Bayesian logistic regression. A spectrum of priors includes optimistic, neutral, and pessimistic priors, along with priors informed from earlier clinical trials. Secondary endpoints (KRT-free days and hospital-free days) were assessed using zero–one inflated beta regression. Results The posterior probability of benefit comparing an accelerated versus a standard KRT initiation strategy for the primary endpoint suggested no important difference, regardless of the prior used (absolute difference of 0.13% [95% credible interval [CrI] − 3.30%; 3.40%], − 0.39% [95% CrI − 3.46%; 3.00%], and 0.64% [95% CrI − 2.53%; 3.88%] for neutral, optimistic, and pessimistic priors, respectively). There was a very low probability that the effect size was equal or larger than a consensus-defined minimal clinically important difference. Patients allocated to the accelerated strategy had a lower number of KRT-free days (median absolute difference of − 3.55 days [95% CrI − 6.38; − 0.48]), with a probability that the accelerated strategy was associated with more KRT-free days of 0.008. Hospital-free days were similar between strategies, with the accelerated strategy having a median absolute difference of 0.48 more hospital-free days (95% CrI − 1.87; 2.72) compared with the standard strategy and the probability that the accelerated strategy had more hospital-free days was 0.66. Conclusions In a Bayesian reanalysis of the STARRT-AKI trial, we found very low probability that an accelerated strategy has clinically important benefits compared with the standard strategy. Patients receiving the accelerated strategy probably have fewer days alive and KRT-free. These findings do not support the adoption of an accelerated strategy of KRT initiation.