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Synthetic supramolecular polymers as artificial extracellular matrix for stem cell expansion towards organoids.

Periodic Reporting for period 1 - SUPRAforORGANS (Synthetic supramolecular polymers as artificial extracellular matrix for stem cell expansion towards organoids.)

Reporting period: 2019-02-01 to 2021-01-31

One of the most urgent challenges in medicine is to devise new strategies for replacing organs. The number of organ replacements not only exceeds by far the supply of organs available for transplantation but is also likely to increase dramatically. Stem cells are a promising tool due to their capacity to proliferate and to differentiate into mature cells of various types; therefore, in principle stem cells could be used to replace any organ in the body.

The fate of stem cells is governed by the microenvironment (or niche) they foster, which offers the main point of control. Unfortunately, the lack of an optimum extracellular matrix (ECM) that closely mimics the in vivo microenvironments to promote differentiation of stem cells is the main limitation of this technology. On this basis, the objective of this project is to develop an artificial ECM based on a hydrogel form by synthetic supramolecular polymers to achieve a system that can support the growth of stem cells into organoids. Importantly, supramolecular polymers are dynamic since their monomers are bound by non-covalent interactions. This property will allow cells to actively adapted the hydrogel, inducing both depolymerisation and reassembly to continuously support the growing organoids.

In summary, the project has achieved to develop a strategy to prepare BTA hydrogels with tunable stiffness, and also found a new technology to bind chemical functionalities to BTA supramolecular polymer. In the future, the performance of these approaches to induce stem cell differentiation need to be evaluated.
SUPRAforORGANS has delivered two significant results that pave the way for the application of 1,3,5-benzene-tricarboxamides (BTAs) based supramolecular polymers for the design of artificial extracellular matrix:

• One of the most significant parameters of the extracellular matrix is its stiffness, which has a central role in guiding the differentiation of cells. Therefore, it is of paramount importance to design strategies that enable to regulate the stiffens of hydrogels. BTA monomers give rise to weak hydrogels due to fibre entanglement with a storage modulus of ca. 20 Pa at 2 wt%. In SUPRAforORGANS, we have developed a method to prepare BTA hydrogels with tuneable stiffness by using an analogue of the natural polymer hyaluronic acid (HA). HA is a polysaccharide that is present in the extracellular matrix of all tissues because it takes part in the regulation of cellular migration and proliferation. By using our HA analogue, the storage modulus of BTA hydrogels can be increased up to 50 times, thereby allowing a wide range of stiffens that are required to direct the stem cell differentiation towards different types of specialized cells.

• In general, the only method currently available to incorporate chemical functionalities into supramolecular polymers is by covalently binding them to the supramolecular monomers. Therefore, the affinity of such molecules for the polymer fibres depends on the interaction strength between the supramolecular monomers. This strategy usually yields to functionalities strongly bonded to the polymer fibres. In SUPRAforORGANS, we aimed to find a strategy that allows attaching chemical moieties to BTA supramolecular polymers with the desired interaction strength between a molecule having the selected chemical functionality and the polymer. Importantly, BTA water-soluble supramolecular polymers require hydrophobic chains in the vicinity of the core to protect their hydrogen-bonded networks from water, thereby giving rise to hydrophobic pockets in the polymer. We found that hydrophobic molecules can interact with these pockets. This strategy could be applied to decorate BTA fibres with different chemical functionalities in a straightforward way. Furthermore, the interaction strength of such interaction could be control by the chemical nature of the hydrophobic part of the guest molecule. This approach will be ideal for attaching different biological to the polymers fibres since it has been shown that some biomolecules required to be more strongly bound to the fibres than others.
SUPRAforORGANS has delivered two relevant strategies that point toward realistic prospects for the application of supramolecular polymers for the preparation of artificial ECM that could be applied for the differentiation of stem cells. Additional, since these technologies are based on reversible non-covalent interactions, an infinite number of artificial matrixes can be rapidly prepared with a minimal synthetic effort to optimize the desired property by only changing the type and ratio of the components. We believed that further investigation of supramolecular polymers could tackle problems like organ shortage.