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Significant advancements in regenerative medicine stem cell research

Regenerative medicine

Regenerative medicine is the area of biomedical science and medicine, focused on development of scientific and clinical approaches and cell therapies to repair or replace pathological cells, tissues or organs (appearing in the body due to disease or injury) by generating and employing stem cells for producing of new tissues and organs.

What are embryonic stem cells?

Due to their unique property of stem cells, regenerative medicine has the great interest in using of these cells. These unspecialized embryonic cells have the inherent unlimited potential to generate into various types of specialized cells of the body: blood cells, nervous cells of brain, skin cells, bone cells, muscle cells etc. The embryonic stem cells don’t possess any specific functions in the body, except just one, but very important – repairing of the body after damage or disease. However, the only natural source of embryonic stem cells are early-stage embryos (also blastocysts), which creates severe ethical issues in the use of human embryos.

Induced pluripotent stem cells

Fortunately, the new option for using stem cells in biology and medicine appeared just 15 years ago. It was the greatest discovery in regenerative medicine of reprogramming of somatic cells, resulted in simultaneous invention and following fast development of the technology of induced pluripotent stem cells (iPSCs) by Takahashi and Yamanaka in 2006 [1]. These scientists generated embryonic-like pluripotent stem cells from mouse embryonic and adult fibroblasts by introducing just four 4 genes or nuclear factors of reprogramming: Oct3/4, Sox2, c-Myc, and Klf4, under conditions of embryonic stem cell culture. These genes are responsible for expression of transcription factors. For this gene transfer, retroviral vectors were employed. Retroviral vectors are obtained from retroviruses, which have the unique capability to transform their single-stranded RNA genome into a double-stranded DNA. That new DNA molecule can integrate into the genome of dividing target cells. Retroviral transduction has been widely used for cancer and stem cell research.Researcher can insert various genes (for example, nuclear factors of reprogramming) into mammalian cells by employing RNA-genome of retroviruses.

As a result of this work, the newly generated iPSCs had the morphology and growth properties of embryonic stem cells, expressing their marker proteins. This research showed that the development of differentiated adult cells can be reversible just by introducing key genes of transcription factors. This process resets those cells in the extremely early stage of development in which they possessed pluripotency. The great significance of this excellent research has been confirmed by awarding of 2012 Nobel Prize in Physiology and Medicine.

This breakthrough discovery with invention of a new technology allowed indispensable capability of regenerative medicine for reprogramming mature somatic cells into an embryonic-like pluripotent state after transferring four genes, resulting in producing of iPSCs, demonstrating properties of stem-like cells (pluripotency etc).

By the way, the idea to generate human iPSCs has long preliminary history of research with several milestones [2], including nuclear reprogramming for cloning frogs (1962), the development of mouse stem cells (1981), reprogramming of fibroblasts into muscle cells (1987), establishing culture conditions for mouse embryonic stem cells and identifying factors of pluripotency (1988), first cloning of mammal (1997), generation of human embryonic cells and establishing their optimal culture conditions [1998], discovery of nuclear factors of reprogramming (2001), generation of mouse iPSCs (2008) etc.

Advantages and problems of using iPSCs

Due capability of iPSCs for differentiation into variety of cell types in the body, obviously, much less ethical issues should appear in using human somatic cells in comparison with human embryonic stem cells. This provides much more opportunities for using this technology in development of effective therapies of human diseases and pathological conditions.

In the beginning of era of reprogramming of somatic cells, scientists recognized that there is the link between pluripotency and tumorigenicity [3]. Surprisingly, there is no such problem nowadays, mostly due to improvement of quality of all components, employed in the iPSC technology and the working protocol itself.

Due to iPSCs can be prepared from and for patients themselves, iPSC technology provides regenerative medicine with autografts, and allows avoiding any graft rejection reactions. However, this is not true in the case of using iPSC from donors, due to variety of HLA genes (encoding HLA proteins) in population. HLA is an important molecule on cellular surface; it enables T cell of the immune system to differentiate between “self” and “foreign” proteins in the body, creating a major problem in employing reprogrammed cells from a donor. Currently, scientists propose two effective approaches to “cheat” immune system and produce universal iPSCs: 1) by deleting HLA expression and 2) by suppressing activity of NK cells [4].

 

The use of iPSCs in regenerative medicine and its perspectives

Since the revolutionary discovery of phenomena of reprogramming of somatic cells, iPSC technology has greatly advanced regenerative medicine, modeling and drug discovery of poorly understood and poorly treated diseases. There are enormous amount of scientific reports and clinical trials, focused on regenerative cell therapy of various human diseases of central and peripheral nervous system (spinal cord injury, Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, schizophrenia, dementia, multiple sclerosis, spinomuscular atrophy etc) [2, 5, 6, 7], heart (cardiomyopathy, heart failure) [8,9], eyes (age-related macular degeneration, corneal endothelial dysfunction, retinitis pigmentosa) [10, 11], blood (thrombocytopenia) [12], liver (chronic liver disease) [13, 14], gastrointestinal tract (ulcer) [15], pancreas (diabetes) [16] skin (dystrophic epidermolysis bullosa) [17], bones (bone injury) [18], various types of cancer [19, 20] etc.

References

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  2. Okano H, Yamanaka S. Mol Brain. 2014 Mar 31;7:22. doi: 10.1186/1756-6606-7-22.
  3. Knoepfler PS. Stem Cells. 2009 May;27(5):1050-6. doi: 10.1002/stem.37.
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  5. Ooi L, Dottori M, Cook AL, Engel M, Gautam V, Grubman A, Hernández D, King AE, Maksour S, Targa Dias Anastacio H, Balez R, Pébay A, Pouton C, Valenzuela M, White A, Williamson R. Neuroscientist. 2020 Oct-Dec;26(5-6):438-454. doi: 10.1177/1073858420912404.
  6. Wang F, Cheng L, Zhang X. Neurosci Bull. 2021 Nov;37(11):1625-1636. doi: 10.1007/s12264-021-00751-3.
  7. Luttrell SM, Smith AST, Mack DL. Muscle Nerve. 2021 Oct;64(4):388-403. doi: 10.1002/mus.27360.
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  9. Paci M, Penttinen K, Pekkanen-Mattila M, Koivumäki JT. J Cardiovasc Pharmacol. 2020 Dec 15;77(3):300-316. doi: 10.1097/FJC.0000000000000972.
  10. Orive G, Santos-Vizcaino E, Pedraz JL, Hernandez RM, Vela Ramirez JE, Dolatshahi-Pirouz A, Khademhosseini A, Peppas NA, Emerich DF. Prog Retin Eye Res. 2019 Jan;68:67-82. doi: 10.1016/j.preteyeres.2018.10.002.
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  12. Nakamura S, Sugimoto N, Eto K. Dev Growth Differ. 2021 Feb;63(2):178-186. doi: 10.1111/dgd.12711.
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  16. Wang P, Karakose E, Choleva L, Kumar K, DeVita RJ, Garcia-Ocaña A, Stewart AF. Front Endocrinol (Lausanne). 2021 Jul 16;12:671946. doi: 10.3389/fendo.2021.671946.
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