**Acknowledgements**

recellularized DC-ECMs exhibited myocardium, vessel-like structures, intracellular Ca2+ transients (CaiT), spontaneous heart contractions and significant response to numerous drug

MSCs could mobilize into circulating blood and be recruited to the injury site, which was consistent with the evidence that numbers of MSCs were increased considerably in peripheral blood [75]. Several approaches were used in an attempt to investigate this cell recruitment event. It was unexpected to find that ECM was indispensable for the homing of MSCs toward sites of injury [76]. The homing effect could be inhibited through adding inhibitor of serine proteases and leupeptin to ECM, which illustrated the key role of matrix remodelling in MSC migration. In addition, evidence also indicated that exposing MSCs to injury-associated ECM prior to transplantation could augment the efficiency of MSCs' intrinsic tropism for injury [77].

As resident stem cells and progenitor cells could be activated to participate tissue regeneration after injury [78,79], ECM designed for cell seeding should also benefit the growth of host cells and support the function of endogenous cells. Encouragingly, evidence suggested that host cells could respond to ECM in the site of injury in vivo. Firstly, immune responses were elicited

within 3 days after implantation. Then there were indications of myogenesis in the muscle injury area, which was confirmed by morphology and myosin heavy chain positive staining

Furthermore, accumulating data suggested that human mesenchymal stem cells (hMSCs) could modulate immune system response through their paracrine effect and then create a pro-regenerative environment in situ. Their paracrine effects could be optimized through encapsulating hMSCs into protective ECM [81]. The recruitment of endogenous macrophag‐ es and the M1/M2 polarization were modulated by the trophic factors secreted by hMSCs, which was possibly capable of counteracting the hostile environment and sustaining tissue regeneration. This cell-friendly microenvironment could also be established by administra‐ tion of ECM alone. Increased stem cell tropism, revascularization, and improved cardiac function induced by chitosan-based ECM were observed in ischemic myocardium [82], which may be attributing to the mechanical support provided by ECM and the therapeutic

The ECM is not only a simple scaffold that provides physical supports for stem cells but also a dynamic and complex environment that is capable of regulating cell behaviours. Although the application of natural or synthetic ECM with the aim to enhance therapeutic effects of stem cells is highly appealing for promoting regenerative processes, issues related to efficiency and safety limit their translational use as regenerative medicine. Further identifying specific

cells throughout the entire ECM

interventions [74].

[80].

**4.2. Support the function of endogenous cells**

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

in hosts, which was identified by the quickly infiltrated CD68+

biomolecules enriched by ECM [83–85].

**5. Future perspectives**

This work was partially supported by grants from the National Natural Science Foundation of China (81371620, 81320108014), Tianjin Natural Science Foundation (14JCZDJC35200) and the Program for Changjiang Scholars and Innovative Research Team in University (IRT13023).
