Damaged endothelial progenitor cells (EPCs) are associated with poor prognosis in diabetic myocardial infarction (DMI). Our previous studies revealed that an impaired Sonic hedgehog (Shh) pathway contributes to insufficient function in diabetic EPCs; however, the roles of the Shh pathway in diabetic EPC apoptosis under basal and hypoxic/ischemic conditions remain unknown. Therefore, the present study investigated whether Shh revitalized diabetic EPCs and consequently improved the deteriorative status of DMI. For this purpose, streptozotocin injection was used in male C57/BL6 mice to induce type-1 diabetes, and diabetic EPCs were isolated from the bone marrow. Apoptosis, cell function, and protein expression were investigated in EPCs in vitro . Mouse hearts were injected with adenovirus Shh-modified diabetic EPCs (DM-EPC Shh ) or control DM-EPC Null immediately after coronary artery ligation in vivo . Cardiac function, capillary numbers, fibrosis, and cell apoptosis were then detected. First, the in vitro results demonstrated that the apoptosis of diabetic EPCs was reduced following treatment with Shh protein for 24 h, under normal or hypoxic conditions. BMI1 proto-oncogene (Bmi1), an antiapoptotic protein found in several cells, was reduced in diabetic EPCs under normal or hypoxic conditions, but was upregulated after Shh protein stimulation. When Bmi1-siRNA was administered, the antiapoptotic effect of Shh protein was significantly reversed. In addition, p53, a Bmi1-targeted gene, was demonstrated to mediate the antiapoptotic effect of the Shh/Bmi1 pathway in diabetic EPCs. The Shh/Bmi1/p53 axis also enhanced the diabetic EPC function. In vivo , Shh-modified diabetic EPCs exhibited increased EPC retention and decreased apoptosis at 3 days post-DMI. At 14 days post-DMI, these cells presented enhanced capillary density, reduced myocardial fibrosis and improved cardiac function. In conclusion, the present results demonstrated that the Shh pathway restored diabetic EPCs through the Shh/Bmi1/p53 axis, suppressed myocardial apoptosis and improved myocardial angiogenesis, thus reducing cardiac fibrosis and finally restoring myocardial repair and cardiac function in DMI. Thus, the Shh pathway may serve as a potential target for autologous cell therapy in diabetic myocardial ischemia.

cell−cell communication, the invasion of pathogens. [1] Many bacteria have evolved specific recognition structures such as fimbriae that bind to host cell glycoconjugates, and these strong affinities of the macromolecular glycans with the bacteria receptors are mainly the result of polyvalent interactions. [2] Controlling the recognition between bacteria and surfaces of glycopolymer based polyvalent scaffolds that constitute the "glycocode" is essential to further understand these processes and to develop anti-infection strategies. [3] Inflamed tissue exhibits several degrees above body temperature due to an increased metabolic rate, [4] which may provide a stimulus for controlling the sweet-talking of bacteria with polyvalent scaffolds. Therefore, to design thermoresponsive polyvalent scaffolds that optimally mimic and adapt to the dynamics of receptors on bacteria membrane would enable intervention in infection caused by bacteria. [5] To date, all thermo-triggerable polyvalent scaffolds are relied on the combination of lower critical solution temperature (LCST)responsive polymers and choice of sugar moieties. [3b,6] For example, Schmidt et al. have recently found the binding affinity of LCST glycopolymers increases above their LCST. [6a] Such Specific recognition and strong affinities of bacteria receptors with the host cell glycoconjugates pave the way to control the bacteria aggregation and kill bacteria. Herein, using aggregation-induced emission (AIE) molecules decorated upper critical solution temperature (UCST) polyvalent scaffold (PATC-GlcN), an approach toward visualizing bacteria aggregation and controlling bacteria-polyvalent scaffolds affinities under temperature stimulus is described. Polyvalent scaffolds with diblocks, one UCST block PATC of polyacrylamides showing a sharp UCST transition and typical AIE behavior, the second bacteria recognition block GlcN of hydrophilic glucosamine modified polyacrylamide, are prepared through a reversible addition and fragmentation chain transfer polymerization. Aggregated chain conformation of poly valent scaffolds at temperature below UCST induces the aggregation of E. coli ATCC8739, because of the high density of glucosamine moieties, whereas beyond UCST, the hydrophilic state of the scaffolds dissociates the bacteria aggregation. The sweet-talking of bacteria toward the polyvalent scaffolds can be visualized by the fluorescent imaging technique, simultaneously. Due to the specific recognition of polyvalent scaffolds with bacteria, the photothermal agent IR780 loaded PATC-GlcN shows the targeted killing ability toward E. coli ATCC8739 in vitro and in vivo under NIR radiation.The ORCID identification number(s) for the author(s) of this article can be found under https://doi.org/10.1002/smll.202107374.

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