**2. Why extracellular matrix is necessary for stem cell therapy**

With the capacity of self-renewal and differentiation, stem cells have shown promising potential in regenerative medicine and tissue engineering. So far, stem cell transplantation have been proposed as future therapies for degenerative diseases or injury, including Alz‐ heimer's disease [10], type 1 diabetes [11], Parkinson's disease [12], cardiac disease [13], muscle damage [14] and many others [15–17]. However, some studies showed that stem cell therapy only had modest improvement, which could be attributed to the fact that transplanted cells were unable to survive and adapt in the diseased area. For instance, low cell retention and engraftment and remarkably cell death after transplantation have been observed by using bioluminescence imaging (BLI) [18].

Though it is not clear what signals and underlying pathways cause the acute donor cell death following transplantation, increasing evidence suggests that that a supportive microenviron‐ ment is of crucial importance for stem cell survival, proliferation and differentiation [5,19]. For this reason, the strategy to seed stem cells on biomaterials that mimic the biochemical and biophysical properties of native niche could be a viable solution to the above mentioned problems [20] and optimize functional recovery of injured tissue (**Figure 1**). For instance, Matrigel, a product derived from the Engelbroth-Holm-Swarm (EHS) mouse sarcoma, is one of the most commonly used plate-coating materials for stem cell culture in vitro and effectively applied vehicles for transplanted stem cells [21]. Mounting evidence has demonstrated that Matrigel could affect cell fate in a variety of dimensions [21,22]. However, Matrigel is a complex with unknown variable matrices and numerous mixed growth factors, which makes it impossible for us to get further insights into the interplay of stem cells and ECM. Besides, another reason for safety concern is that Matrigel has been reported contaminated with Lactate Dehydrogenase Elevating Virus [23]. To avoid these problems, artificially synthetic ECM with both high purity and defined components in qualitative and quantitative measures for safe application is strongly demanded [24,25]. Recently, developments in engineered ECM-based microenvironments have gradually exhibited their ability for directing stem cell behaviours, such as adhesion, proliferation, and differentiation [26].

**Figure 1. Extracellular matrix(ECM) is necessary for stem cell therapy.** A form of apoptosis, called "anoikis", will be initiated once interactions between stem cells and ECM are cut off. Re-establish the connection between ECM and de‐ tached cells could increase cell viability and promote function recovery of injured tissue [4]. Reprinted by permission of the publisher.
