**3. Influence of the extracellular matrix on stem cell behaviour**

adapt atthe siteof administrationwhere there is lackoffunctionalvascularnetworktotransport

Through enhancing cell retention and engraftment after transplantation, modulating stem cell fate, and promoting functional vasculature formation, co-transplantation stem cells with natural or synthetic ECM that mimic natural extracellular milieu could be a potentially powerful tool to break the current bottleneck and maximize the effectiveness of stem cell therapy [7–9]. These strategies provide considerable hope for the development of stem cell therapy in degenerative diseases. This chapter will provide the insights into the interaction between stem cells and ECM, as well as current knowledge and involvement of stem cell therapy. Moreover, we will discuss the strategy of co-transplantation stem cells and ECM for

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

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,

blood, supply oxygen and nutrients, and remove metabolites [6].

324 Composition and Function of the Extracellular Matrix in the Human Body

tissue regeneration with enhanced therapeutic efficacy.

such as adhesion, proliferation, and differentiation [26].

bioluminescence imaging (BLI) [18].

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

Extracellular matrix (ECM), acting in conjunction with the biophysical properties and bio‐ chemical extracellular stimuli, is critical to regulate stem cell maintenance and differentiation [27,28]. It has been reported that a form of apoptosis, called "anoikis", would be initiated when interactions between stem cells and ECM were cut off [19]. Great effort has been made in an attempt to detail the mechanisms, which provides some key information for cell–ECM interplay. For example, recent study investigated changes of genes' expression after cell detachment by using PCR Array [2]. In that study, researchers found that adhesion molecules expression had no significant difference between cultured human embryonic stem cell-derived

**Figure 2. ECM and cell adhesion related gene-expression patterns of hESC-EC at different conditions.** Expression of more than 4-fold changes genes of hESC-ECs in Matrigel compared with hESC-ECs in PBS [4]. Reprinted by permis‐ sion of the publisher.

endothelial cells (hESC-ECs) and enzymatically dispersed hESC-ECs suspended in Matrigel. However, a series of ECM and adhesion molecules-specific genes was considerably downregulated in hESC-EC suspended in PBS (**Figure 2**). These gene-expression data indicated that adding ECM to detached cells could reverse genes down-regulation of ECM pathway, cell adhesion molecules pathway, ECM and adhesion signalling.

#### **3.1. Biochemical stimulus**

The assignment of cell fate results from a response to sophisticated extracellular signals [29,30]. There is mounting evidence suggesting that ECM could deliver numerous soluble and immobilized factors that play vital roles in making the fate choice between self-renewal and lineage commitment [31]. Further insights and exquisite control of signals transported by ECM could provide opportunities for enhancing the regenerative efficacy in both in vitro and in vivo and further accelerating the translation of basic science to the clinical setting.
