Bone Marrow To Other Cell Types

Some cell-type conversions using bone marrow-derived stem cells have been shown to occur across what was previously considered to be germ-line boundaries (i.e., mesoderm to endoderm). In this situation, it is not evident whether the cell must first become a different stem cell and then differentiate along a different pathway or if it directly transdifferentiates to another phenotype. However, some doubt has been cast on these observations, and it has been suggested that the result is caused by an artifact from fusion of the circulating hematopoietic stem cells with resident cells. (See chapters 3, 9, and 32 in this volume for a description of these types of transdifferentiations.)

De-differentiation as a Prerequisite for Transdifferentiation

A question arises: If transdifferentiation is to occur, must the parent cell lose its phenotype before acquiring a new identity? In some examples (IPE to lens), there is an intermediate phe-notype in which the cells do not express markers for either cell type (Figure 10-1B). However, examples of direct transdifferentiation do occur. Perhaps the best example is the transdifferentiation of pancreas to liver (pancreatic exocrine to hepatocyte) (Figure 10-1A). Whether a cell undergoes transdifferentiation directly, through a de-differentiated state, or through a stem cell may vary depending on which cell types are being studied (Figure 10-1). In other words, does the parent cell contain the necessary information to change its phenotype directly, or does it require the synthesis of new proteins? In direct transdifferentiation, the cell's competency is already established, and it is the removal of an inhibitor or the addition of an activator that pushes the fate of the cell over the final hurdle. For de-differentiation and stem cell intermediates, it may be necessary to establish the competency of the parent cell before it can undergo transdifferentiation. Further studies examining the transdifferentiation potential

IPE Intermediate Lene

Muscla

Figure 10-1. Examples of transdifferentiation. Transdifferentiation car occur in different stages: (A) Transdifferentiation of pancreas to liver can occur without cell division or an intermediate phenotype. (B) Transdifferentiation of pigment epithelium to lens requires an intermediate stage in which the cel does not possess the characteristics of either phenotype. (C) The pluripotency of stem cells is shown by their ability to convert to different cell lineages. In this example, the switch is direct and there is no conversion to another tissue-specific stem cell.

Muscla

Figure 10-1. Examples of transdifferentiation. Transdifferentiation car occur in different stages: (A) Transdifferentiation of pancreas to liver can occur without cell division or an intermediate phenotype. (B) Transdifferentiation of pigment epithelium to lens requires an intermediate stage in which the cel does not possess the characteristics of either phenotype. (C) The pluripotency of stem cells is shown by their ability to convert to different cell lineages. In this example, the switch is direct and there is no conversion to another tissue-specific stem cell.

of individual transcription factors and various cell types will help to bring about an understanding of the rules of transdifferentiation.

How to Change a Cell's Phenotype Experimentally

The ability to change a cell's phenotype will greatly facilitate the design of therapies for diseases such as diabetes, liver failure, and neurodegenerative disorders (e.g., Parkinson's disease). We suggest six steps to follow to try and change a cell's phenotype experimentally.

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