Introduction

Embryonic stem cells isolated from the inner cell mass of a blastocyst can become any cell from the three germ layers. It is this potential to produce any cell type needed that excites the world of regenerative medicine as these cells can potentially be used to create any tissue from scratch.

Stem cells have two defining properties, the capacity to self-renew, and pluripotency; the ability to differentiate into any cell from the three germ layers.

Self renewal is the ability to undergo division without differentiation, thereby producing identical daughter cells to maintain the stem cell population. To maintain the stem cell number, only one cell needs to become a stem cell; the other daughter cell differentiates to another cell type. The stem cell niche where these cells reside protects them from various differentiation signals. As the cells divide, limited space or axis of division can cause one cell to lose contact with the niche, enabling it to be receptive to differentiation signals and progress down a particular lineage.

The Stem Cell Niche



The other main property of stem cells is their capacity to produce cells from the ectoderm, mesoderm and endoderm. Stem cells can differentiate into many different lineages as they express low levels of numerous genes needed to commit cells to various cell types. As a stem cell's progeny progressed down a certain lineage, chromatin remodelling shuts down genes associated with other cell fates the cell could have gone down.

Control of Self Renewal and Pluripotency

The properties of self renewal and pluripotency are tightly regulated by intrinsic factors such as transcription factors, and extrinsic signals including growth factors. Key intrinsic factors are the transcription factors Oct4, Sox2 and Nanog. Oct4, a Pou domain transcription factor that binds ATGCAAAT, maintains the pluripotent state by inhibiting Cdx2, a factor that promotes trophectoderm differentiation, the first defined lineage to form. Sox2 is a HMG family transcription factor that often binds with Oct4 and is vital for epiblast and extraembryonic endoderm formation. Nanog is also key for the regulation of stem cells, playing roles in preventing endoderm formation and in self renewal.

Extrinsic factors such as growth factors also play a vital role in controlling the stem cell state. FGF2 signalling is needed for self renewal and Wnt signalling has been shown to be important to maintain the undifferentiated state.

Intrinsic and Extrinsic factors controlling stem cells



Embryonic Stem Cells for Therapy

The use of stem cells to treat disease is one principal focus of regenerative medicine. Not only could stem cells provide a source of cells and tissues for transplantation, they can also be used to study embryonic development, produce disease models, test drug toxicity, test differentiation protocols and other therapies. Embryonic stem cells can differentiate into any cell type of the body and can be cultured indefinitely, so they have a high potential to produce desired cell populations to overcome donor transplant shortages. 

In some degenerative diseases when stem cell function is impaired, these could be treated by replacing the defective cells with embryonic stem cells. As implanting undifferentiatied embryonic cells into the body could result in tumour formation or undesired cell types being formed, many agree the way forward is to pre-differentiate cells into the desired cell type before implantation.

Often the protocols for differentiation try to mimic the developmental pathway seen in vivo. To differentiate embryonic stem cells into hormone-producing pancreatic cells, a 5 stage protocol to mirror development is used. Various growth factors are added at each stage. Stage 1- activin A and Wnt, stage 2- FGF10 and CYC, stage 3- FGF10, CYC and retinoic acid, stage 4- DAPT, stage 5- IGF-1 and hepatocyte growth factor.

Difficulties in Stem Cell Therapy

While embryonic stem cell therapy is promising for treatment of various conditions, there are many issues to consider before these therapies become commonly used. One concern is the issue of immunorejection. This problem could be overcome by producing 'universal donor' cells which have MHC expression knocked-out to prevent rejection. 

The extensive differentiation capacity of embryonic stem cells along with the gaps in knowledge concerning differentiation pathways means the formation of tumours is a big concern in stem cell therapy. A much deeper understanding of developmental pathways is needed to overcome this issue. 

Another consideration to stem cell therapy is how cells will react to being implanted into suboptimal, degenerative environments. If these cells are to be used for regeneration, the disease state is often aberrent compared to normal tissue. Additionally, cells may need to be seeded into biomaterials to accurately mimic the tissue or organ needed. Therefore, it is critical to test stem cell therapies in the appropriate environment before implantation.

Induced Pluripotent Stem cells (iPS cells)

Embryonic stem cells bring with them serious ethical implications surrounding their derivation and concerns of tumour formation. A relatively new alternative is the use of iPS cells. These are somatic cells such as fibroblasts which are reprogrammed to have the characteristics of embryonic stem cells by the transfection of transcription factors Oct4, Sox3, Klf4 and c-myc. While iPS cells exhibit the morphological and differentiation characteristics of embryonic cells, they do not have the same ethical concerns, meaning a major advantage to progress with stem cell biology. One potential of iPS cells is the use of these in personalised medicine, using patient's own cells to produce regenerative stem cell therapy.

References

Boyer, L., Mathur, D., Jaenisch, R. (2006) Molecular control of pluripotency. Curr. Op. Gen. Dev. 16: 455-462

Chambers I., Smith A. (2004) Self-renewal of teratocarinoma and embryonic stem cells. Oncogene 23(43):7150-7160

Daley, G. (2002) Prospects for stem cell therapeutics; myths and medicine. Current Opinion in Genetics and Development 12: 607-613

 

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