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Turning straw into gold: directing cell fate for regenerative medicine

Key Points

  • Both in vitro study and transplantation therapy in human patients require large numbers of cells of a desired type. Often, such cells cannot be readily obtained from primary sources (such as patient biopsies or cadavers). As a result, the development of methods to convert plentiful, readily available cell types into the types needed for study and therapy is highly desirable.

  • One strategy for producing cells of a desired type is termed 'directed differentiation'. In this process, a pluripotent stem cell, such as an embryonic stem cell or induced pluripotent stem cell, is pushed through a series of cell-fate decisions in order to achieve the desired fate.

  • Cell-fate decisions can be directed in vitro using a variety of methods, including the application of growth factors or small molecules, and through the use of co-culture systems.

  • Another strategy for producing desired cells is to begin with fully differentiated cells of a readily available type, such as fibroblasts, and convert them directly into the desired cell type through a process called 'reprogramming'.

  • A reprogramming strategy usually relies on the overexpression of key transcription factors that can activate the transcriptional programme that leads to the desired cellular phenotype.

  • Cells produced by either reprogramming or directed differentiation must be carefully evaluated and compared with their endogenous counterparts to determine the extent to which the cells produced in vitro are the functional equivalent of those produced in vivo.

  • Both directed-differentiation and reprogramming methods are currently extremely inefficient, and typically generate cells with an immature or embryonic phenotype. These challenges must be overcome in order for cells produced by these methods to achieve their full potential.

  • In spite of these limitations, two Phase I clinical trials on the safety of transplantable cells generated in vitro are currently under way, providing evidence of the promise of the methods described in this Review for research and medicine.

Abstract

Regenerative medicine offers the hope that cells for disease research and therapy might be created from readily available sources. To fulfil this promise, the cells available need to be converted into the desired cell types. We review two main approaches to accomplishing this goal: in vitro directed differentiation, which is used to push pluripotent stem cells, including embryonic stem cells or induced pluripotent stem cells, through steps similar to those that occur during embryonic development; and reprogramming (also known as transdifferentiation), in which a differentiated cell is converted directly into the cell of interest without proceeding through a pluripotent intermediate. We analyse the status of progress made using these strategies and highlight challenges that must be overcome to achieve the goal of cell-replacement therapy.

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Figure 1: The central strategies of regenerative medicine.
Figure 2: Directed differentiation.
Figure 3: Reprogramming.

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Acknowledgements

We apologize to authors whose studies could not be cited owing to space limitations. Work in the laboratory of D.M. is funded by the US National Institutes of Health, The Leona M. and Harry B. Helmsley Charitable Trust, the Juvenile Diabetes Research Foundation and the Howard Hughes Medical Institute.

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Correspondence to Douglas Melton.

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Glossary

Directed differentiation

The process by which pluripotent stem cells are induced to assume a particular cell fate, through the application of specific culture conditions designed to produce cell-fate changes similar to those observed in the formation of the target cell type in vivo.

Reprogramming

(Also referred to as transdifferentiation.) The direct interconversion of one fully differentiated cell type to another without a pluripotent or multipotent intermediate, often achieved through transcription-factor overexpression.

Transdetermination

A switch in commitment from one lineage to another, closely related lineage that occurs in a multipotent stem or progenitor cell.

Embryonic stem cells

(ESCs). Pluripotent stem cells derived from the inner cell mass of a mammalian embryo.

Induced pluripotent stem cells

(iPSCs). Pluripotent stem cells derived from somatic cells by reprogramming.

Ectoderm

One of the three germ layers formed in early embryonic development; this layer gives rise to tissues including the skin and the nervous system.

Mesoderm

One of the three embryonic germ layers; the mesoderm gives rise to connective tissue, the heart and blood, among other tissue types.

Endoderm

One of the three embryonic germ layers; this layer produces tissues such as the gut, liver, pancreas and lungs.

Spontaneous differentiation

The process by which pluripotent stem cells take on a mixture of cell fates in vitro on transfer from media containing factors that maintain pluripotency to media lacking such factors.

Embryoid bodies

Clusters of pluripotent stem cells, usually grown in suspension culture, that are undergoing spontaneous differentiation.

Multiplicity of infection

The ratio of viral particles present in a transduction experiment divided by the number of target cells present.

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Cohen, D., Melton, D. Turning straw into gold: directing cell fate for regenerative medicine. Nat Rev Genet 12, 243–252 (2011). https://doi.org/10.1038/nrg2938

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