HDAC Inhibitors as Epigenetic Regulators

Histological analysis indicated that such functional benefits by CMMP treatment were accompanied by remuscularization (Fig. a synthetic cell-mimicking microparticle (CMMP) that recapitulates stem cell functions in tissue repair. CMMPs carry similar secreted proteins and membranes as genuine cardiac stem cells do. In a mouse model of myocardial infarction, injection of CMMPs leads to the preservation of viable myocardium and augmentation of cardiac functions similar to cardiac stem cell therapy. CMMPs (derived from human cells) do not Vandetanib trifluoroacetate stimulate T-cell infiltration in immuno-competent mice. In conclusion, CMMPs act as synthetic stem cells which mimic the paracrine and biointerfacing activities of natural stem cells in therapeutic cardiac regeneration. Multiple types of adult stem cells, such as mesenchymal stem cells, cardiac stem cells (CSCs), and endothelial progenitor cells have entered clinical investigations worldwide1,2,3,4,5,6. Differentiation of injected cells into the host tissues has been reported. However, these sporadic events could not explain the therapeutic benefits seen in animal models and human trials7,8. Later on, the field realized that one important mode of therapeutic action is the secretion of paracrine factors by injected stem cells that act like mini-drug pumps to promote endogenous repair9,10. Moreover, stem cell membranes are not null Vandetanib trifluoroacetate in the repair process: contact with the injected stem cells triggers intracellular protective/regenerative pathways in the host cells11,12. On the basis of these two aspects, we proposed a core-shell design of a therapeutic microparticle (MP) which mimicked stem cell biointerfacing during regeneration. This particle, named cell-mimicking MP (CMMP), contained control-released stem cell factors in its polymeric core and was cloaked with stem cell membrane fragments on the surface. Our hypothesis is that CMMP can exert similar regenerative outcomes as real CSCs but are superior to the later since they are more stable during storage and do not stimulate T-cell immune reaction since they are not real cells. In the present study, we report for the first time a poylmer MP which emulates CSC functions during tissue repair. In a mouse model of myocardial infarction, injection of CMMPs led to preservation of viable myocardium and augmentation of cardiac functions similar to CSC therapy. CMMPs (derived from human cells) did not stimulate T-cell infiltration in immuno-competent mice, suggesting their excellent safety profile. Although our first application targeted the heart, the CMMP strategy represents a platform technology that can be applied to multiple stem cell types and the repair of various organ systems. Results Physiochemical and biological properties of CMMPs The biochemical design and work model of CMMPs were outlined in Fig. 1a. Briefly, Control MP1 were fabricated from Vandetanib trifluoroacetate poly(lactic-co-glycolic acid) (PLGA) and Rabbit Polyclonal to MYL7 conditioned media of human CSCs which were isolated from human hearts using the cardiosphere method as previously described13,14 (Supplementary Fig. 1). The conditioned media contains various growth factors secreted by CSCs10. CSCs have been tested and proven safe and effective in Phase I/II clinical trials1,2,3. After that, MPs (Texas red succinimidyl ester-labelled; Fig. 1b, red) were cloaked with the membrane fragments of CSCs (green fluorescent DiO-labelled; Fig. 1b, green) to become the final product CMMP (Fig. 1c, red particle with green coat). Fluorescent imaging revealed there is no specific DiO outer layer fluorescence on Texas red succinimidyl ester-labelled MPs (Control MP1) after 30?min co-culture (Supplementary Fig. 2). Scanning electron microscopy (SEM) revealed the effective CSC membrane cloaking on CMMPs (Fig. 1e) but not on non-cloaked MPs (Control MP1; Fig. 1d). As another control particle, Control MP2 was fabricated by cloaking empty PLGA particles with CSC membranes. We fabricated CMMPs, Control MP1 and Control MP2 with sizes similar to those of real CSCs (Fig. 1h). As an indicator of successful membrane cloaking, flow cytometry analysis confirmed the expression of major human CSC markers (for example, CD105, CD90) on CMMPs and Control MP2 but not on Control MP1 (Figs 1f,g and ?and2).2). Overall, both CMMPs and Control MP2 carried similar surface antigens as CSCs did (Fig. 1i). Membrane cloaking did not affect the release of CSC factors (namely vascular endothelial growth factor, insulin-like growth factor-1.