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Derive and conquer: sourcing and differentiating stem cells for therapeutic applications

Key Points

  • Human embryonic stem cells (ESCs) hold great promise for regenerative medicine. However, many technical hurdles and unanswered questions remain before this research can be safely translated into real treatments in the clinic. These range from cell sourcing and the efficient production of differentiated cell derivatives to the ethical issues related to the use of human embryos.

  • Safety comes first when it comes to human clinical trials. This requires human ESC derivatives to be free of human and animal pathogens, particularly if feeder cells and/or other animal products are used for co-culture. The derivatives also have to undergo extensive safety testing to ensure that they are non-tumorigenic.

  • Immune rejection is another major obstacle associated with the transplantation of cells and tissues. Several strategies are currently being explored to generate histocompatible human ESC derivatives, including somatic cell nuclear transfer, parthenogenesis and cellular reprogramming.

  • The destruction of human embryos to generate ESCs remains a major source of ethical controversy. Several strategies have been proposed to solve this problem. These include the use of cell reprogramming, parthenogenesis, altered nuclear transfer and the use of biopsied cells removed from embryos using a technique similar to pre-implantation genetic diagnosis.

  • For clinical studies, large enough quantities of the appropriate replacement cell type will need to be generated under well-defined and reproducible conditions using traceable reagents. Purity, yield and functionality of the cells will also need to be optimized.

  • Non-embryonic tissues may also be an important source of stem cells. Multipotent and pluripotent cells have been successfully isolated from bone marrow, adipose tissue, skin, teeth, testes, amniotic fluid and umbilical-cord blood, among others. These stem cells have been shown to differentiate into a variety of important cell types, and have the advantage of being histocompatible with the individual from which they were derived.

Abstract

Although great progress has been made in the isolation and culture of stem cells, the future of stem-cell-based therapies and their productive use in drug discovery and regenerative medicine depends on two key factors: finding reliable sources of multipotent and pluripotent cells and the ability to control their differentiation to generate desired derivatives. It is essential for clinical applications to establish reliable sources of pathogen-free human embryonic stem cells (ESCs) and develop suitable differentiation techniques. Here, we address some of the problems associated with the sourcing of human ESCs and discuss the current status of stem-cell differentiation technology.

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Figure 1: Possible ways to generate immune-compatible derivatives of pluripotent cells.
Figure 2: In vitro avenues to differentiation of embryonic stem cells (ESCs).

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Correspondence to Irina Klimanskaya.

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I.K. and R.L. are employees of Advanced Cell Technologies, a biotechnology company in the field of stem cells and regenerative medicine.

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Glossary

Pluripotent

In cell biology this term is usually used to indicate that pluripotent cells can develop into derivatives of all three germ layers.

Organ-derived stem cells

These are often called 'adult' or 'somatic' stem cells; adult in this case meaning 'differentiated' or 'other than embryonic', because multipotent stem cells have also been isolated from extraembryonic and perinatal tissues.

Feeder cells

Cells of a different type and often different species that are used in a co-culture system to help maintain embryonic stem cells (ESCs) undifferentiated and mitotically inactivated to prevent overgrowing. Traditionally mouse embryonic fibroblasts were used as feeders for mouse and human ESCs, but in anticipation of using human ESC derivatives in the clinic, novel human ESC culture systems have been developed that use human cell lines as feeders or no feeder cells at all.

Teratoma

A rare tumour type that typically arises in the gonads and demonstrates mixed cellular populations of all three embryonic germ layers. Investigators can assess the differentiation capacity of stem cells by injection of pluripotent cells into laboratory animals and inducing the formation of teratomas in situ.

Bromodeoxyuridine

(BrdU). 5-bromo-2-deoxyuridine is a synthetic analogue of the nucleoside thymidine. BrdU is used to label proliferating cells within a given time-frame in vitro or in vivo. It incorporates into the newly replicated DNA strands and can be detected with anti-BrdU antibodies.

Blastocyst

A blastocyst is a multi-cell structure formed by a developing mammalian embryo at the early stages of development that looks like a spheroid formed by an outer cell layer — trophectoderm, a cavity — a blastocoel and an inner cell mass (ICM). In further development, a trophoblast gives rise to extraembryonic tissues, while the ICM develops into a new organism. Cells of the ICM are pluripotent and can also produce embryonic stem cells.

Parthenote

Parthenote, parthenogenesis is derived from the Greek 'parthenos', which means virgin. In this article, it pertains to activated unfertilized oocytes that are capable of undergoing the cleavage division and forming blastocysts. It is accepted that parthenote embryos in mammals are not capable of forming extraembryonic tissues and thus cannot complete normal development.

Reprogramming

Occurs naturally in regenerative organisms (dedifferentiation). Induced experimentally in mammalian cells by nuclear transfer, cell fusion or genetic manipulation of in vitro culture.

Mulitpotent

Can form multiple lineages that can give rise to several kinds of cells, tissues or structures, for example, haematopoietic stem cells.

Cybrid

Is a cell produced by the fusing of a eukaryotic cell with an enucleated cell or a cytoplast.

Totipotent

Sufficient to form an entire organism. Totipotency is seen in zygote and plant meristem cells, but has not demonstrated for any vertebrate stem cell.

Morula

A stage of early embryonic development when an embryo consists of a cluster of cells.

C-peptide

C-peptide is a product of proinsulin when it is split, producing insulin and C-peptide after release from the pancreas.

Embryoid bodies

Spherical cell clusters observed after spontaneous or induced differentiation of embryonic stem cells in culture. Embryoid bodies show differentiation that recapitulates the early stages of mammalian embryonic development, including cell types derived from endoderm, mesoderm and ectodermal lineages.

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Klimanskaya, I., Rosenthal, N. & Lanza, R. Derive and conquer: sourcing and differentiating stem cells for therapeutic applications. Nat Rev Drug Discov 7, 131–142 (2008). https://doi.org/10.1038/nrd2403

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