Embryonic stem cells have huge potential in the field of tissue engineering and regenerative medicine as they hold the capacity to produce every type of cell and tissue in the body. In theory, the treatment of human disease could be revolutionized by the ability to generate any cell, tissue, or even organ, 'on demand' in the laboratory. This work reviews the history of murine and human ES cell lines, including practical and ethical aspects of ES cell isolation from pre-implantation embryos, maintenance of undifferentiated ES cell lines in the cell culture environment, and differentiation of ES cells in vitro and in vivo into mature somatic cell types. Finally, we discuss advances towards the clinical application of ES cell technology, and some of the obstacles which must be overcome before large scale clinical trials can be considered.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2184.2004.00298.x

Embryonic stem cells.

Transplantation studies in mice and rats have shown that human embryonic-stem-cell-derived cardiomyocytes (hESC-CMs) can improve the function of infarcted hearts, but two critical issues related to their electrophysiological behaviour in vivo remain unresolved. First, the risk of arrhythmias following hESC-CM transplantation in injured hearts has not been determined. Second, the electromechanical integration of hESC-CMs in injured hearts has not been demonstrated, so it is unclear whether these cells improve contractile function directly through addition of new force-generating units. Here we use a guinea-pig model to show that hESC-CM grafts in injured hearts protect against arrhythmias and can contract synchronously with host muscle. Injured hearts with hESC-CM grafts show improved mechanical function and a significantly reduced incidence of both spontaneous and induced ventricular tachycardia. To assess the activity of hESC-CM grafts in vivo, we transplanted hESC-CMs expressing the genetically encoded calcium sensor, GCaMP3 (refs 4, 5). By correlating the GCaMP3 fluorescent signal with the host ECG, we found that grafts in uninjured hearts have consistent 1:1 host–graft coupling. Grafts in injured hearts are more heterogeneous and typically include both coupled and uncoupled regions. Thus, human myocardial grafts meet physiological criteria for true heart regeneration, providing support for the continued development of hESC-based cardiac therapies for both mechanical and electrical repair.

/pdf/human-es-cell-derived-cardiomyocytes-electrically-couple-and-2y42mhjbs7.pdf

Human ES-cell-derived cardiomyocytes electrically couple and suppress arrhythmias in injured hearts

Telomerase is an attractive cancer target as it appears to be required in essentially all tumours for immortalization of a subset of cells, including cancer stem cells. Moreover, differences in telomerase expression, telomere length and cell kinetics between normal and tumour tissues suggest that targeting telomerase would be relatively safe. Clinical trials are ongoing with a potent and specific telomerase inhibitor, GRN163L, and with several versions of telomerase therapeutic vaccines. The prospect of adding telomerase-based therapies to the growing list of new anticancer products is promising, but what are the advantages and limitations of different approaches, and which patients are the most likely to respond?

Telomerase and cancer therapeutics

Antibodies are engineered by replacing one or more amino acids of a parent antibody with non cross-linked, highly reactive cysteine amino acids. Antibody fragments may also be engineered with one or more cysteine amino acids to form cysteine engineered antibody fragments (ThioFab). Methods of design, preparation, screening, and selection of the cysteine engineered antibodies are provided. Cysteine engineered antibodies (Ab), optionally with an albumin-binding peptide (ABP) sequence, are conjugated with one or more drug moieties (D) through a linker (L) to form cysteine engineered antibody-drug conjugates having Formula I: Ab-(L-D)p I where p is 1 to 4. Diagnostic and therapeutic uses for cysteine engineered antibody drug compounds and compositions are disclosed.

Cysteine engineered antibodies and conjugates

Auristatin peptides, including MeVal-Val-Dil-Dap-Norephedrine (MMAE) and MeVal-Val-Dil-Dap-Phe (MMAF), were prepared and attached to Ligands through various linkers, including maleimidocaproyl-val-cit-PAB. The resulting ligand drug conjugates were active in vitro and in vivo.

Monomethylvaline compounds capable of conjugation to ligands

The human telomerase reverse transcriptase (hTERT) promoter is known to selectively drive transgene expression in many human cancer cells expressing hTERT, the catalytic component of the telomerase ribonucleoprotein complex. We have created a conditionally replicative adenovirus where the viral E1A gene, which is required for viral replication, is under the control of the hTERT promoter (AdhTERTp-E1A). In vitro studies with AdhTERTp-E1A virus on a variety of normal and tumor cell lines have shown that viral genome replication and productive infection is primarily restricted to telomerase-positive tumor cells. Lytic replication was not observed in normal primary fibroblast and epithelial cell lines tested. In vivo administration of the virus into nude mice bearing human liver or prostate tumor xenografts produced significant tumor reduction and, in some cases, resulted in complete tumor regression. AdhTERTp-E1A virus did not actively express E1A in normal mouse liver, in contrast to a control oncolytic vector in which the CMV promoter (AdCMVp-E1A) was driving the E1A gene. In addition, AdhTERTp-E1A virus produced no apparent toxicity to the liver in systemically injected mice. The hTERT promoter-driven oncolytic virus also produced significantly less toxicity to freshly cultured human hepatocytes. These studies demonstrate that an oncolytic virus driven by the telomerase promoter can be used to effectively kill a wide variety of cancer cell types and has the potential to treat primary and metastatic cancer of diverse origins.

Conditionally replicative adenovirus driven by the human telomerase promoter provides broad-spectrum antitumor activity without liver toxicity.

Genes that are up- or down-regulated during differentiation provide important leverage by which to characterize and manipulate early-stage pluripotent stem cells. Over 35,000 unique transcripts have been amplified and sequenced from undifferentiated human embryonic stem cells, and three types of differentiated progeny. Statistical analysis of the assembled transcripts identified genes that alter expression levels as differentiation proceeds. The expression profile provides a marker system that has been used to identify particular culture components for maintaining the undifferentiated phenotype. The gene products can also be used to promote differentiation; to assess other relatively undifferentiated cells (such as cancer cells); to control gene expression; or to separate cells having desirable characteristics. Manipulation of particular genes can be used to forestall or focus the differentiation process, en route to producing a specialized homogenous cell population suitable for human therapy.

Genes that are up- or down-regulated during differentiation of human embryonic stem cells

This disclosure provides a system for qualifying embryonic stem cells intended for human therapy. A comprehensive sequencing project has identified important markers that are characteristic of undifferentiated pluripotent cells. Combinations of these markers have been used to screen feeder cells, media additives, and culture conditions that promote rapid expansion of stem cells without differentiation. By measuring undifferentiated stem cell markers, and markers formed by early progenitors such as stromal cells, the user can quantitate the proportion and extent of differentiation. This establishes standardized criteria for master cell banks and cell cultures that can then be used to produce therapeutic cell populations and medicaments for use in regenerative medicine.

Standardization of growth conditions for human embryonic stem cells intended for use in regenerative medicine

This disclosure provides a system for qualifying embryonic stem cells intended for human therapy. A large-scale sequencing project has identified important markers that are characteristic of undifferentiated pluripotent cells. Combinations of these markers can be used to validate the self-renewing capacity of ES cells, and their ability to differentiate into tissue types suitable for regenerative medicine. The marker system of this invention has been used to screen feeder cells, media additives, and culture conditions that promote proliferation of stem cells without differentiation. A culture system optimized by following these markers is suitable for rapid expansion of undifferentiated cells from existing lines, or the derivation of new lines that are equally apposite for clinical use.

A marker system for characterizing undifferentiated human embryonic stem cells

Production of human embryonic stem cell-derived cellular product for therapeutic use

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