Stereoselective carbohydrate synthesis[1,2]has experiencedimmense strides in the last few years,benefiting from assimilatingknowledge at the frontiers of modern synthetic concepts.On thisfront,the dual but parallel dev...Stereoselective carbohydrate synthesis[1,2]has experiencedimmense strides in the last few years,benefiting from assimilatingknowledge at the frontiers of modern synthetic concepts.On thisfront,the dual but parallel development of radical catalysis in glycosylations[3–6]and the tapping of weak noncovalent interactions(NCIs)[7–11]for catalytic stereocontrol in stereoselective carbohydrate synthesis are of immense interest.It is important to emphasize that these two broad pillars were previously relativelyunheard of in thefield of classical carbohydrate chemistryfiveyears ago,but since then they have substantially established themselves in the mild and efficient construction of glycosidic linkages[12].The precise catalytic control of the stereochemistry of nativeglycosidic linkages had historically been challenging,as this seemingly simple C–O bond forming step required the concurrent tackling of two fundamental selectivity challenges(Fig.1a):Namelythe anomeric selectivity challenge to construct the C1 acetal andthe site-selectivity challenge[13,14]to discriminate the numeroushydroxyl groups on a carbohydrate polyol substrate.展开更多
Human induced pluripotent stem cell(hiPSC)-derived kidney organoids have prospective applications ranging from basic disease modelling to personalised medicine.However,there remains a necessity to refine the bio-physi...Human induced pluripotent stem cell(hiPSC)-derived kidney organoids have prospective applications ranging from basic disease modelling to personalised medicine.However,there remains a necessity to refine the bio-physical and biochemical parameters that govern kidney organoid formation.Differentiation within fully-controllable and physiologically relevant 3D growth environments will be critical to improving organoid reproducibility and maturation.Here,we matured hiPSC-derived kidney organoids within fully synthetic self-assembling peptide hydrogels(SAPHs)of variable stiffness(storage modulus,G′).The resulting organoids con-tained complex structures comparable to those differentiated within the animal-derived matrix,Matrigel.Single-cell RNA sequencing(scRNA-seq)was then used to compare organoids matured within SAPHs to those grown within Matrigel or at the air-liquid interface.A total of 13,179 cells were analysed,revealing 14 distinct clusters.Organoid compositional analysis revealed a larger proportion of nephron cell types within Transwell-derived organoids,while SAPH-derived organoids were enriched for stromal-associated cell populations.Notably,dif-ferentiation within a higher G’SAPH generated podocytes with more mature gene expression profiles.Addi-tionally,maturation within a 3D microenvironment significantly reduced the derivation of off-target cell types,which are a known limitation of current kidney organoid protocols.This work demonstrates the utility of syn-thetic peptide-based hydrogels with a defined stiffness,as a minimally complex microenvironment for the selected differentiation of kidney organoids.展开更多
文摘Stereoselective carbohydrate synthesis[1,2]has experiencedimmense strides in the last few years,benefiting from assimilatingknowledge at the frontiers of modern synthetic concepts.On thisfront,the dual but parallel development of radical catalysis in glycosylations[3–6]and the tapping of weak noncovalent interactions(NCIs)[7–11]for catalytic stereocontrol in stereoselective carbohydrate synthesis are of immense interest.It is important to emphasize that these two broad pillars were previously relativelyunheard of in thefield of classical carbohydrate chemistryfiveyears ago,but since then they have substantially established themselves in the mild and efficient construction of glycosidic linkages[12].The precise catalytic control of the stereochemistry of nativeglycosidic linkages had historically been challenging,as this seemingly simple C–O bond forming step required the concurrent tackling of two fundamental selectivity challenges(Fig.1a):Namelythe anomeric selectivity challenge to construct the C1 acetal andthe site-selectivity challenge[13,14]to discriminate the numeroushydroxyl groups on a carbohydrate polyol substrate.
基金funded by the Irish Government's Program for Research in Third-Level Institutions,Cycle 4,National Development Plan 2007-2013supported by the European Union Structural Fund
基金This publication has emanated from research conducted with the financial support of Science Foundation Ireland(SFI)co-funded under the European Regional Development Fund under Grant Number 13/RC/2073_P2+1 种基金The authors acknowledge support from Science Foundation Ireland(16/IA/4584)19/FFP/6833.J.K.W.would also like to acknowledge Royal Society of Chemistry grant(M19-6613).
文摘Human induced pluripotent stem cell(hiPSC)-derived kidney organoids have prospective applications ranging from basic disease modelling to personalised medicine.However,there remains a necessity to refine the bio-physical and biochemical parameters that govern kidney organoid formation.Differentiation within fully-controllable and physiologically relevant 3D growth environments will be critical to improving organoid reproducibility and maturation.Here,we matured hiPSC-derived kidney organoids within fully synthetic self-assembling peptide hydrogels(SAPHs)of variable stiffness(storage modulus,G′).The resulting organoids con-tained complex structures comparable to those differentiated within the animal-derived matrix,Matrigel.Single-cell RNA sequencing(scRNA-seq)was then used to compare organoids matured within SAPHs to those grown within Matrigel or at the air-liquid interface.A total of 13,179 cells were analysed,revealing 14 distinct clusters.Organoid compositional analysis revealed a larger proportion of nephron cell types within Transwell-derived organoids,while SAPH-derived organoids were enriched for stromal-associated cell populations.Notably,dif-ferentiation within a higher G’SAPH generated podocytes with more mature gene expression profiles.Addi-tionally,maturation within a 3D microenvironment significantly reduced the derivation of off-target cell types,which are a known limitation of current kidney organoid protocols.This work demonstrates the utility of syn-thetic peptide-based hydrogels with a defined stiffness,as a minimally complex microenvironment for the selected differentiation of kidney organoids.
