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Dynamic control of hydrogel crosslinking via sortase-mediated reversible transpeptidation

机译：通过分选酶介导的可逆转肽段动态控制水凝胶交联

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Cell-laden hydrogels whose crosslinking density can be dynamically and reversibly tuned are highly sought-after for studying pathophysiological cellular fate processes, including embryogenesis, fibrosis, and tumorigenesis. Special efforts have focused on controlling network crosslinking in poly(ethylene glycol) (PEG) based hydrogels to evaluate the impact of matrix mechanics on cell proliferation, morphogenesis, and differentiation. In this study, we sought to design dynamic PEG-peptide hydrogels that permit cyclic/reversible stiffening and softening. This was achieved by utilizing reversible enzymatic reactions that afford specificity, biorthogonality, and predictable reaction kinetics. To that end, we prepared PEG-peptide conjugates to enable sortase A (SrtA) induced tunable hydrogel crosslinking independent of macromer contents. Uniquely, these hydrogels can be completely degraded by the same enzymatic reactions and the degradation rate can be tuned from hours to days. We further synthesized SrtA-sensitive peptide linker (i.e., KCLPRTGCK) for crosslinking with 8-arm PEG-norbornene (PEG8NB) via thiol-norbornene photocrosslinking. These hydrogels afford diverse softening paradigms through control of network structures during crosslinking or by adjusting enzymatic parameters during on-demand softening. Importantly, user-controlled hydrogel softening promoted spreading of human mesenchymal stem cells (hMSCs) in 3D. Finally, we designed a bis-cysteine-bearing linear peptide flanked with SrtA substrates at the peptide’s N- and C-termini (i.e., NH2-GGGCKGGGKCLPRTG-CONH2) to enable cyclic/reversible hydrogel stiffening/softening. We show that matrix stiffening and softening play a crucial role in growth and chemoresistance in pancreatic cancer cells. These results represent the first dynamic hydrogel platform that affords cyclic gel stiffening/softening based on reversible enzymatic reactions. More importantly, the chemical motifs that affords such reversible crosslinking were built-in on the linear peptide crosslinker without any post-synthesis modification.
机译：人们迫切需要具有交联密度可以动态和可逆地调节的充满细胞的水凝胶，以研究病理生理细胞的命运过程，包括胚胎发生，纤维化和肿瘤发生。专门的工作集中在控制基于聚乙二醇（PEG）的水凝胶中的网络交联，以评估基质力学对细胞增殖，形态发生和分化的影响。在这项研究中，我们试图设计允许循环/可逆的硬化和软化的动态PEG肽水凝胶。这是通过利用可逆的酶促反应实现的，该反应可提供特异性，生物正交性和可预测的反应动力学。为此，我们制备了PEG-肽共轭物，以使分选酶A（SrtA）诱导的可调水凝胶交联独立于大分子单体含量。独特的是，这些水凝胶可以通过相同的酶促反应完全降解，降解速度可以从数小时调节至数天。我们进一步合成了SrtA敏感肽接头（即KCLPRTGCK），可通过硫醇-降冰片烯光交联与8臂PEG-降冰片烯（PEG8NB）交联。这些水凝胶通过在交联过程中控制网络结构或在按需软化过程中调节酶参数，提供了多种软化范例。重要的是，用户控制的水凝胶软化促进了人类间充质干细胞（hMSCs）在3D中的扩散。最后，我们设计了一种带有双半胱氨酸的线性肽，在该肽的N和C末端（即NH2-GGGCKGGGKKPRPRTG-CONH2）两侧带有SrtA底物，以实现循环/可逆的水凝胶硬化/软化。我们表明，基质的硬化和软化在胰腺癌细胞的生长和化学抗性中起着至关重要的作用。这些结果代表了第一个动态水凝胶平台，该平台基于可逆的酶促反应提供了环状凝胶硬化/软化作用。更重要的是，提供这种可逆交联的化学基序内置在线性肽交联剂上，无需任何合成后修饰。

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