Induced Pluripotency (Ips) Cells In Disease Modelling And Regenerative Medicine

IPSC stands for Induced Pluripotent Stem Cells. These are cells that were once fully differentiated somatic cells that have been reprogrammed through deactivating endogenous genes that are active in the cells differentiated form and activating other genes discovered to be pivotal in dictating whether or not a cell has the ability to differentiate into a wide range of cells (pluripotency). DNA undergoing epigenetic modification is thought to be vital for a cell to regain and stably maintain its pluripotency (1). The fact that these cells are in many ways similar to human embryonic stem cells yet do not require the use, or indeed the loss of human embryos is welcomed by the scientific community as it bypasses many ethical concerns raised in the past. Also, bearing in mind that these IPSCs can be obtained from healthy cells of the patient with a disorder (that could be treated with IPSCs the problem of rejection and an immune response is dealt with to a greater extent than with the use of human embryonic stem cells (2). There is a challenge in the fact that there are minute differences in the patterns of gene expression between embryonic stem cells and IPSCs thought to be because of introduction of exogenous genes being introduced into the genome. The implications of this from a functionality point of view remain unclear (3).

What can IPSCs be used for?

1) Disease Modelling

The discovery of IPSCs has opened up a wealth of opportunities in terms of disease modelling. These IPSCs can be generated with relative ease in a normal laboratory setting using standard equipment and techniques which is advantageous because it is an improvement on previous, more difficult methods to derive pluripotency within a cell such as fusing together somatic cells with embryonic stem cells (4). It is also worth noting that IPSCs can be obtained from a variety individuals that differ in gender, age and ethnicity but are healthy. This would provide an immediate supply of cells that could be used for drug screening to assess factors such as toxicity of a drug to a specific cell line almost mirroring the effect the drug could have in the human body. This gets around the problem of a difference in response between (other) animals and humans to drugs.

Often what is found is that interaction with the drug in animals during drug testing can be very different to the drug interaction in humans in terms of its effect. This in turn has the potential to result in inaccurate drug predictions which aren???t specific to the pathology at hand. Therefore, as IPSCs can be used to model the human cellular environment relatively accurately, it means drug production can be more efficient and drug administration more informed. An example of this is the generation of hepatocytes with different cytochrome p450 enzymes (from people for the IPSC bank) which would be valuable for predicting how the liver would react to new drugs because of the different cytochrome p450 enzymes (2).

The use of IPSCs is especially important when creating disease models, using cells directly from the patient, that do not have an alternative in vitro or animal modelling method due to the sheer complexity of the medical conditions at hand. Obtaining cell lines that are diseased or mutated from patients is of benefit as it allows us to blueprint the development of unique medical conditions, thereby helping us to tackle them. IPSC lines with disease have been produced from patients with pathologies including type one diabetes mellitus (5), amyotrophic lateral sclerosis, spinal muscular atrophy, Parkinson???s disease and many more (6).

Without IPSCs it was often extremely difficult to gain a more significant understanding into a disease. One example of this was in rheumatoid Arthritis where much of the insight regarding pathophysiology came through mice models through collagen induced arthritis. Unfortunately however it was revealed that these animal models were not very representative of the actual situation in humans with rheumatoid arthritis (7). Also, it has often been suggested understanding from animal models has infrequently resulted in success in a clinical setting (8)

2) Regenerative Medicine

IPSCs offer long term prospects in regenerative medicine and cellular therapy. Again, as mentioned earlier the origin of these cells can be from the very patient looking to be treated thus reducing the risk of immunological rejection. The role of IPSCs in regenerative medicine is still in its early stages, much research is being carried out for many purposes pertaining to their safety (see later) in regenerative medicine.

A condition that shows promise through the possible application of IPSCs is rheumatoid arthritis. IPSCs can undergo directed differentiation in order to mature into chondrocytes producing cartilage and osteocytes producing the bone to counteract the effects of rheumatoid arthritis and osteoarthritis (9). The cells from the patient that were specifically used for reprogramming were fibroblast-like synoviocytes (FLS). The reprogramming was done via a viral vector which carried with it four factors; c-Myc, Klf4, Sox2 and Oct4. The reason for the use of fibroblast-like synoviocytes was because they have an important role in the pathophysiology of rheumatoid arthritis. They were predicted to be viable cells for inducing pluripotency in order to model the disease (10). In a study carried out (9), rheumatoid arthritis FLSs were successfully reprogrammed into IPSCs. This was proven within the study as IPSCs that had not yet differentiated were introduced into the subrenal capsule of SCID beige mice resulting in a successful teratoma formation comprising the ectoderm, mesoderm and endoderm.

While this is good news for sure, there are still many hurdles to overcome before we can maximise the use of IPSCs which are discussed below.

IPSC Challenges to overcome

In the short term IPSCs have proved extremely useful, however, there remains challenges to overcome before we can unlock their full potential.

For the production of IPSCs we have relied mostly on transduction via a retrovirus. This can be problematic as the integration of the virus is quite random bearing in mind IPSCs can have up to 40 different viral integration sites present in their genome resulting in inefficiency. Furthermore, once pluripotency has been induced through a viral vector, during the differentiation process proviruses are silenced. However, these transgenes can become reactivated resulting in oncogenes which could prove fatal. Indeed, when Myc was reactivated in chimeric mice it resulted in tumour formation (11). There is also the risk of mutation in the host genome because on the integration of transgenes. In addition, any proviruses introduced to the cell can have regrettable effects on neighbouring genes within the host again possibly leading to oncogenesis. An example of this is in children with SCID post introduction of haematopoietic stem cells (12).

While there are ongoing efforts in reprogramming cells without potentially dangerous transcription factors such as the Myc family, and this has been successful to an extent if we look at how inducing pluripotency in skin fibroblasts has been carried out with only Sox2, Oct4 using a histone deacetylase inhibitor (13), but when Myc is not used reprogramming is significantly more inefficient.

The issue of immune rejection also remains when IPSCs are retrieved from a bank of IPSCs rather than the patient themselves.

Conclusion

There is no doubt within the scientific community that IPSCs have been extremely beneficial in the recent past in a number of different ways but mainly in the realm of disease modelling, which has been revolutionised. IPSCs are allowing significant improvements in therapeutic strategies to tackle many conditions due to the improvement in the accuracy of models being used that IPSCs facilitate. Although there is a long way to go in terms of their role in cell therapy, significant progress is being made to make IPSCs human friendly through research into alternative and more efficient methods of reintroducing pluripotency.

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