https://repository.kulib.kyoto-u.ac.jp/dspace/bitstream/2433/49782/1/Yamanaka_Cell_131_5.pdf

Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors

Current neural induction protocols for human embryonic stem (hES) cells rely on embryoid body formation, stromal feeder co-culture or selective survival conditions. Each strategy has considerable drawbacks, such as poorly defined culture conditions, protracted differentiation and low yield. Here we report that the synergistic action of two inhibitors of SMAD signaling, Noggin and SB431542, is sufficient to induce rapid and complete neural conversion of >80% of hES cells under adherent culture conditions. Temporal fate analysis reveals the appearance of a transient FGF5(+) epiblast-like stage followed by PAX6(+) neural cells competent to form rosettes. Initial cell density determines the ratio of central nervous system and neural crest progeny. Directed differentiation of human induced pluripotent stem (hiPS) cells into midbrain dopamine and spinal motoneurons confirms the robustness and general applicability of the induction protocol. Noggin/SB431542-based neural induction should facilitate the use of hES and hiPS cells in regenerative medicine and disease modeling and obviate the need for protocols based on stromal feeders or embryoid bodies.

/pdf/highly-efficient-neural-conversion-of-human-es-and-ips-cells-5ewq762oqw.pdf

Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling

Hydrogel delivery systems can leverage therapeutically beneficial outcomes of drug delivery and have found clinical use. Hydrogels can provide spatial and temporal control over the release of various therapeutic agents, including small-molecule drugs, macromolecular drugs and cells. Owing to their tunable physical properties, controllable degradability and capability to protect labile drugs from degradation, hydrogels serve as a platform in which various physiochemical interactions with the encapsulated drugs control their release. In this Review, we cover multiscale mechanisms underlying the design of hydrogel drug delivery systems, focusing on physical and chemical properties of the hydrogel network and the hydrogel-drug interactions across the network, mesh, and molecular (or atomistic) scales. We discuss how different mechanisms interact and can be integrated to exert fine control in time and space over the drug presentation. We also collect experimental release data from the literature, review clinical translation to date of these systems, and present quantitative comparisons between different systems to provide guidelines for the rational design of hydrogel delivery systems.

/pdf/designing-hydrogels-for-controlled-drug-delivery-3k03j5j2j9.pdf

Designing hydrogels for controlled drug delivery.

Stem cell fate is influenced by a number of factors and interactions that require robust control for safe and effective regeneration of functional tissue. Coordinated interactions with soluble factors, other cells, and extracellular matrices define a local biochemical and mechanical niche with complex and dynamic regulation that stem cells sense. Decellularized tissue matrices and synthetic polymer niches are being used in the clinic, and they are also beginning to clarify fundamental aspects of how stem cells contribute to homeostasis and repair, for example, at sites of fibrosis. Multifaceted technologies are increasingly required to produce and interrogate cells ex vivo, to build predictive models, and, ultimately, to enhance stem cell integration in vivo for therapeutic benefit.

/pdf/growth-factors-matrices-and-forces-combine-and-control-stem-4daxw4e632.pdf

Growth Factors, Matrices, and Forces Combine and Control Stem Cells

https://gladstone.org/u/dsrivastava/Articles/Ieda-Cell-2010.pdf

Direct Reprogramming of Fibroblasts into Functional Cardiomyocytes by Defined Factors

Cardiomyocytes derived from human embryonic stem (hES) cells potentially offer large numbers of cells to facilitate repair of the infarcted heart. However, this approach has been limited by inefficient differentiation of hES cells into cardiomyocytes, insufficient purity of cardiomyocyte preparations and poor survival of hES cell-derived myocytes after transplantation. Seeking to overcome these challenges, we generated highly purified human cardiomyocytes using a readily scalable system for directed differentiation that relies on activin A and BMP4. We then identified a cocktail of pro-survival factors that limits cardiomyocyte death after transplantation. These techniques enabled consistent formation of myocardial grafts in the infarcted rat heart. The engrafted human myocardium attenuated ventricular dilation and preserved regional and global contractile function after myocardial infarction compared with controls receiving noncardiac hES cell derivatives or vehicle. The ability of hES cell-derived cardiomyocytes to partially remuscularize myocardial infarcts and attenuate heart failure encourages their study under conditions that closely match human disease.

https://courses.washington.edu/conj504/readings/murry_reading2.pdf

Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts

This invention provides a new procedure for generating cardiomyocyte lineage cells from embryonic stem cells for use in regenerative medicine. Differentiating by way of embryoid body formation or in serum is no longer required. Instead, the stem cells are plated onto a solid substrate, and differentiated in the presence of select factors and morphogens. After enrichment for cells with the appropriate phenotype, the cells are allowed to cluster into cardiac bodies™, which are remarkably homogeneous and suitable for the treatment of heart disease.

Direct differentiation method for making cardiomyocytes from human embryonic stem cells

This invention provides a new procedure for generating cardiomyocyte lineage cells from embryonic stem cells for use in regenerative medicine. Differentiating by way of embryoid body formation or in serum is no longer required. Instead, the stem cells are plated onto a solid substrate, and differentiated in the presence of select factors and morphogens. After enrichment for cells with the appropriate phenotype, the cells are allowed to cluster into cardiac bodiesTM, which are remarkably homogeneous and suitable for the treatment of heart disease.

Method for making high purity cardiomyocyte preparations suitable for regenerative medicine

Heart disease due to myocardial infarction and the ensuing heart failure represent a major unmet medical need. Approved treatments do not prevent loss of cardiac muscle or reduce scar formation, both of which weaken heart function. Cell‐based therapies currently being investigated both preclinically and clinically have the potential to address these underlying problems either by actually replacing lost tissue or by supplying paracrine growth factors that may have multiple beneficial effects such as reduction of inflammation, increase of blood supply, improvement in cell survival, and reduction of scar size. The best cell types, stage of disease to target, and delivery method to improve heart function are currently unclear. The California Institute for Regenerative Medicine supports multiple different cell‐therapy strategies for heart disease, offering hope that improved treatments will be available for patients in the future.

Proceedings: Moving Toward Cell-Based Therapies for Heart Disease: Cell-Based Therapies for Heart Disease

Human embryonic stem cells (hESCs) represent an attractive source for deriving large numbers of definitive and rapidly proliferating human cardiomyocytes for cell-based cardiac repair. Successful a...

Lila R. Collins

Papers

Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts

Direct differentiation method for making cardiomyocytes from human embryonic stem cells

Method for making high purity cardiomyocyte preparations suitable for regenerative medicine

Proceedings: Moving Toward Cell-Based Therapies for Heart Disease: Cell-Based Therapies for Heart Disease

Abstract 553: Human Embryonic Stem Cell-Derived Cardiomyocytes Form Human Myocardium and Improve Cardiac Function in Infarcted Rat Hearts