*3.1.1. Release of soluble factors*

The propagation of soluble signalling molecules controls a great variety of cellular responses, including proliferation [32], polarity [33], migration [34], and differentiation [35]. It has been

**Figure 3. Putative model outlining the controlled nitric oxide (NO)-releasing hydrogel enhances the therapeutic ef‐ fect of adipose derived-mesenchymal stem cells (ADSCs) for myocardial infarction.** Encapsulation of ADSCs by NO-releasing hydrogel prevented transplanted cells effusing from injection positions. NO molecule released from the hydrogel catalyzed by β-galactosidase can facilitate angiogenic cytokines secretion of ADSCs, resulting in promoting angiogenesis, ADSCs survival and cardiac function. β-gal, β-galactosidase [9]. Reprinted by permission of the publish‐ er.

demonstrated that a specific interaction between cells and ECM is required for the ultimate biological response of soluble molecules [29,36,37]. Interactions with ECM can affect the responses of cell toward signalling messengers. For instance, insulin-triggered activation of insulin receptor substrate (IRS) was intensely enhanced in cells cultured on basement mem‐ brane than on collagen I, whereas higher levels of tyrosine phosphorylation of the EGF receptor and Erk was triggered by EGF in cell adhesion to collagen I [36].

In living systems, the coordinated effort among cells, growth factors and ECM is required for the successful tissue regeneration. The ability of manipulating biological signals transduced by ECM in a controlled and spatiotemporal manner that mimic the natural regenerative process could provide specific control over the stem cell-based regenerative therapy [38]. The potential therapeutic effect of a peptide-based ECM with the capacity of controlled release nitric oxide (NO), NapFF-NO, was tested in a mouse model of myocardial infarction [9]. The therapeutic effect of adipose-derived-mesenchymal stem cells (ADSCs) was elevated through co-transplantation with NapFF-NO and on-demand NO release (**Figure 3**). Additionally, the administration of growth factors within the context of the ECM niche could accentuate their therapeutic effects for tissue repair [39]. It was reported that a recombinant fragment of fibronectin (FN) could significantly enhance the regenerative effects of growth factors in models of chronic wounds and bone defects [40].
