Method for stem cell differentiation in vivo by delivery of morphogenes with mesoporous silica and corresponding pharmceutical active ingredients

Abstract

A pharmaceutical active ingredient for cell differentiation to alleviate cell and cell-related deficiencies in mammals comprising porous silica containing a releasable agent capable of contributing to a cell environment conducive for stem cell differentiation in co-implanted stem cells and / or in endogenous stem cells.

Description

FIELD OF THE INVENTION[0001]The present invention relates to pharmaceutical active ingredients comprising sets composed of stem cells and porous silica, preferably mesoporous silica, containing a defined set of differentiation factors for desired differentiation of different types of cells, and to a method of enhancing survival and control differentiation of transplanted stem cells for regenerative medicine by providing said sets. In particular, the pharmaceutical active ingredients and methods of the invention are preferably used for controlling differentiation of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs); in general, they are also applicable for other stem cells, e.g. tissue-specific stem cells and mesenchymal stem cells.BACKGROUND OF THE INVENTION[0002]Experimental stem cell research has achieved enormous progress during the past few years in generating desired types of cells in vitro, which can be used in regenerative medicine. These in vitro protoco...

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Benefits of technology

[0029]The present inventors have found that human ESCs can be forced to differentiate to neurons by local delivery of the sonic hedgehog agonist purmorphamine (Pur) and retinoic acid (RA) from mesoporous nanoparticles. This approach may therefore be useful for improving initial survival of transplanted stem cells, as well as for achieving desired differentiation of these cells and maintain their long term viability.

[0030]According to one aspect, the present invention provides a method of enhancing cell-survival during implantation of stem cells.

[0076]An additional source for repair of myocardial contractility are skeletal myoblasts (Nomura T, Ueyama T, Ashihara E, et al. Skeletal muscle-derived progenitors capable of differentiating into cardiomyocytes proliferate through myostatin-independent TGF-beta family signaling. Biochem Biophys Res Commun 2008; 365:863-9), although they do not seem to be able to differentiate to cardiomyocytes (Reinecke H, Poppa V, Murry C E. Skeletal muscle stem cells do not transdifferentiate into cardiomyocytes after cardiac grafting. J Mol Cell Cardiol 2002; 34:241-9; Leobon B, Garcin I, Menasche P, et al. Myoblasts transplanted into rat infarcted myocardium are functionally isolated from their host. Proc Natl Acad Sci USA 2003; 100:7808-11). Intravascular delivery or cardiac transplants of multipotent or pre-differentiated cardiogenic cells from these stem cell sources have been shown to promote cardiac structural repair and functional restoration in animal models of myocardial injury (Fukushima S, Coppen S R, Lee J, et al. Choice of cell-delivery route for skeletal myoblast transplantation for treating post-infarction chronic heart failure in rat. PLoS One 2008; 3:e3071; Hendry S L 2nd, van der Bogt K E, Sheikh A Y, et al. Multimodal evaluation of in vivo magnetic resonance imaging of myocardial restoration by mouse embryonic stem cells. J Thorac Cardiovasc Surg 2008; 136:1028-37; Matsuura K, Honda A, Nagai T, et al. Transplantation of cardiac progenitor cells ameliorates cardiac dysfunction after myocardial infarction in mice. J Clin Invest 2009; 119:2204-17; Jin J, Jeong S I, Shin Y M, et al. Transplantation of mesenchymal stem cells within a poly(lactide-co-epsilon-caprolactone) scaffold improves cardiac function in a rat myocardial infarction model. Eur J Heart Fail 2009; 11:147-53; Okura H, Matsuyama A, Lee CM, et al. Cardiomyoblast-like cells differentiated from human adipose tissue-derived mesenchymal stem cells improve left ventricular dysfunction and survival in a rat myocardial infarction model. Tissue Eng Part C Methods 2010; 16:417-25).

[0152]right: the reduced migration of NCSCs (small circles) towards Islets and increased differentiation of NCSCs in the initial location when they were co-transplanted with AMS (black triangle).

Problems solved by technology

However, addition of multiple FGFs, BMP antagonists and Wnt antagonists to the chick embryonic epiblast is not sufficient to induce the expression of the neural marker Sox2, suggesting that still other pathways regulate neural induction (Linker C, Stern CD.

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