Entregas de primeira classe em células: mero acaso, fortuita necessidade ou design inteligente?

segunda-feira, outubro 09, 2023

Genetically engineered mesenchymal stem cells as a nitric oxide reservoir for acute kidney injury therapy

Haoyan Huang Meng Qian Yue Liu Shang Chen Huifang Li Zhibo Han Zhong-Chao Han Xiang-Mei Chen Qiang Zhao Zongjin Li 

Nankai University School of Medicine, China; The Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, the College of Life Sciences, China; National Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, China; Jiangxi Engineering Research Center for Stem Cell, Shangrao, China; Tianjin Key Laboratory of Engineering Technologies for Cell Pharmaceutical, National Engineering Research Center of Cell Products, AmCellGene Co., Ltd, China; Beijing Engineering Laboratory of Perinatal Stem Cells, Beijing Institute of Health and Stem Cells, Health & Biotech Co, China; Tianjin Key Laboratory of Human Development and Reproductive Regulation, Tianjin Central Hospital of Gynecology Obstetrics, Nankai University Affiliated Hospital of Obstetrics and Gynecology, China

Sep 11, 2023


Microscopy image of mesenchymal stem cells (blue) after administration of the drug MGP (red), which can drive the release of nitric oxygen from cells. Image credit: Huang et al. (CC BY 4.0)


Nitric oxide (NO), as a gaseous therapeutic agent, shows great potential for the treatment of many kinds of diseases. Although various NO delivery systems have emerged, the immunogenicity and long-term toxicity of artificial carriers hinder the potential clinical translation of these gas therapeutics. Mesenchymal stem cells (MSCs), with the capacities of self-renewal, differentiation, and low immunogenicity, have been used as living carriers. However, MSCs as gaseous signaling molecule (GSM) carriers have not been reported. In this study, human MSCs were genetically modified to produce mutant β-galactosidase (β-GALH363A). Furthermore, a new NO prodrug, 6-methyl-galactose-benzyl-oxy NONOate (MGP), was designed. MGP can enter cells and selectively trigger NO release from genetically engineered MSCs (eMSCs) in the presence of β-GALH363A. Moreover, our results revealed that eMSCs can release NO when MGP is systemically administered in a mouse model of acute kidney injury (AKI), which can achieve NO release in a precise spatiotemporal manner and augment the therapeutic efficiency of MSCs. This eMSC and NO prodrug system provides a unique and tunable platform for GSM delivery and holds promise for regenerative therapy by enhancing the therapeutic efficiency of stem cells.



Organização de microcompartimentos bacterianos - mero acaso, fortuita necessidade ou design inteligente?

Dissecting the phase separation and oligomerization activities of the carboxysome positioning protein McdB

Joseph L Basalla Claudia A MakJordan A Byrne Maria GhalmiY Hoang Anthony G Vecchiarelli 

Department of Molecular, Cellular, and Developmental Biology, University of Michigan-Ann Arbor, United States; Department of Biological Chemistry, University of Michigan-Ann Arbor, United States

Sep 5, 2023


Droplets of the protein McdB (green) that have phase separated out of solution and will behave like liquids by growing and fusing together. Image credit: Joe Basalla (CC BY 4.0).


Across bacteria, protein-based organelles called bacterial microcompartments (BMCs) encapsulate key enzymes to regulate their activities. The model BMC is the carboxysome that encapsulates enzymes for CO2 fixation to increase efficiency and is found in many autotrophic bacteria, such as cyanobacteria. Despite their importance in the global carbon cycle, little is known about how carboxysomes are spatially regulated. We recently identified the two-factor system required for the maintenance of carboxysome distribution (McdAB). McdA drives the equal spacing of carboxysomes via interactions with McdB, which associates with carboxysomes. McdA is a ParA/MinD ATPase, a protein family well studied in positioning diverse cellular structures in bacteria. However, the adaptor proteins like McdB that connect these ATPases to their cargos are extremely diverse. In fact, McdB represents a completely unstudied class of proteins. Despite the diversity, many adaptor proteins undergo phase separation, but functional roles remain unclear. Here, we define the domain architecture of McdB from the model cyanobacterium Synechococcus elongatus PCC 7942, and dissect its mode of biomolecular condensate formation. We identify an N-terminal intrinsically disordered region (IDR) that modulates condensate solubility, a central coiled-coil dimerizing domain that drives condensate formation, and a C-terminal domain that trimerizes McdB dimers and provides increased valency for condensate formation. We then identify critical basic residues in the IDR, which we mutate to glutamines to solubilize condensates. Finally, we find that a condensate-defective mutant of McdB has altered association with carboxysomes and influences carboxysome enzyme content. The results have broad implications for understanding spatial organization of BMCs and the molecular grammar of protein condensates.