Stem Cells - Induced

Embryology - 11 Dec 2023 Expand to Translate
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Introduction

Mouse- embryonic stem cell signaling regulation

The term "induced stem cell" refers to the new methods of gene introduction and expression that generate stem cells from both embryo and adult tissues.

A useful guide (online PDF document) to stem cells was produced in a report by the National Institute of Health (NIH, USA, May 2000) Stem Cells: A Primer (note large size - 4.84 Mb) and more recently NIH has established a Stem Cell information page.

Some Recent Findings

STAP now discredited.

Directing differentiation of human induced pluripotent stem cells toward androgen-producing Leydig cells rather than adrenal cells^[1]} "Reduced serum testosterone (T), or hypogonadism, affects millions of men and is associated with many pathologies, including infertility, cardiovascular diseases, metabolic syndrome, and decreased libido and sexual function. Administering T-replacement therapy (TRT) reverses many of the symptoms associated with low T levels. However, TRT is linked to side effects such as infertility and increased risk of prostate cancer and cardiovascular diseases. Thus, there is a need to obtain T-producing cells that could be used to treat hypogonadism via transplantation and reestablishment of T-producing cell lineages in the body. T is synthesized by Leydig cells (LCs), proposed to derive from mesenchymal cells of mesonephric origin. Although mesenchymal cells have been successfully induced into LCs, the limited source and possible trauma to donors hinders their application to clinical therapies. Alternatively, human induced pluripotent stem cells (hiPSCs), which are expandable in culture and have the potential to differentiate into all somatic cell types, have become the emerging source of autologous cell therapies. We have successfully induced the differentiation of hiPSCs into either human Leydig-like (hLLCs) or adrenal-like cells (hALCs) using chemically defined culture conditions. Factors critical for the development of LCs were added to both culture systems. hLLCs expressed all steroidogenic genes and proteins important for T biosynthesis, synthesized T rather than cortisol, secreted steroid hormones in response to dibutyryl-cAMP and 22(R)-hydroxycholesterol, and displayed ultrastructural features resembling LCs. By contrast, hALCs synthesized cortisol rather than T. The success in generating hiPSC-derived hLLCs with broad human LC (hLC) features supports the potential for hiPSC-based hLC regeneration."

Is Stimulus-triggered fate conversion of somatic cells into pluripotency (STAP) Real? RIKEN Panel Finds Misconduct in Reprogrammed Stem Cell Papers press release April 1, 2014 | Science April 2014 | Japanese research institute has opened an investigation into this groundbreaking stem cell study after concerns were raised about its credibility. The RIKEN investigation follows allegations on blog sites about the use of duplicated images in Obokata’s papers, and numerous failed attempts to replicate her results. Nature

The Nobel Prize in Physiology or Medicine 2012 was awarded jointly to Sir John B. Gurdon and Shinya Yamanaka "for the discovery that mature cells can be reprogrammed to become pluripotent"
Shinya Yamanaka Yamanaka Factors are a set of 4 transcription factors when introduced into cells induces stem cell formation. Search PubMed

More recent papers
This table allows an automated computer search of the external PubMed database using the listed "Search term" text link. This search now requires a manual link as the original PubMed extension has been disabled. The displayed list of references do not reflect any editorial selection of material based on content or relevance. References also appear on this list based upon the date of the actual page viewing. References listed on the rest of the content page and the associated discussion page (listed under the publication year sub-headings) do include some editorial selection based upon both relevance and availability. More? References \| Discussion Page \| Journal Searches \| 2019 References \| 2020 References Search term: Induced Stem Cells \| OCT4 \| SOX2 \| \| KLF4 \| cMyc

Older papers
These papers originally appeared in the Some Recent Findings table, but as that list grew in length have now been shuffled down to this collapsible table. See also the Discussion Page for other references listed by year and References on this current page. John Gurdon used nuclear transplantation and cloning to show that the nucleus of a differentiated somatic cell retains the totipotency necessary to form a whole organism. 2003 Current Biology Interview PMID 14521852 2009 Interview - "The birth of cloning" PMID 19132124 Search PubMed The tumorigenicity of human embryonic and induced pluripotent stem cells ^[2] "Until recently, it was assumed that human induced pluripotent stem cells (HiPSCs) would behave like their embryonic counterparts in respect to their tumorigenicity. However, a rapidly accumulating body of evidence suggests that there are important genetic and epigenetic differences between these two cell types, which seem to influence their tumorigenicity." iPS cells produce viable mice through tetraploid complementation^[3] "Here we report the generation of several iPS cell lines that are capable of generating viable, live-born progeny by tetraploid complementation. These iPS cells maintain a pluripotent potential that is very close to ES cells generated from in vivo or nuclear transfer embryos. We demonstrate the practicality of using iPS cells as useful tools for the characterization of cellular reprogramming and developmental potency, and confirm that iPS cells can attain true pluripotency that is similar to that of ES cells."

Induced Pluripotent Stem Cell

2016 Interview with Shinya Yamanaka

<html5media width="480" height="360">https://www.youtube.com/embed/--o1aux_htA</html5media>

Development - 2016 Interview with Shinya Yamanaka (inducible Stem Cells)

YouTube Links
Note - this may include both internal and external movie links. Links: One Minute Embryology \| 2016 Yamanaka inducible stem cells \| Embryology Channel

Prof. Shinya Yamanaka ia a Nobel laureate and the developer of induced stem cells.

Rat induced pluripotential stem cell protocol^[4]

(iPS cell) A reprogrammed adult stem cell to form an embryonic stem cell, from which tissues or whole animals can develop. Can be generated by the expression of just four specific transcription factors.

Links: Nature Jul09 | ABC - Mice pups bred from adult stem cells

Yamanaka Factors

Yamanaka Factors^[5]^[6] Are a set of 4 transcription factors when introduced into cells induces stem cell formation. These four transcription factors can be expressed from doxycycline (dox)-inducible lentiviral vectors.

OCT4

Octamer-binding transcription factor 3/4
Transcription factors containing the POU homeodomain

Links: OMIM - OCT4

SOX2

Early mouse Sox2 expression.^[7]

Sry-related HMG-Box gene 2.
Sox2 is first expressed in very early (morula, blastocyst) development.
Forms a trimeric transcription complex with OCT4.
Gene targets - YES1, FGF4, UTF1 and ZFP206.

Links: | Sox | OMIM - SOX2

KLF4

Kruppel-like factor 4, zinc finger protein, transcription factor which acts as both an activator and repressor.
alternative names: Epithelial zinc finger protein EZF or Gut-enriched krueppel-like factor

Links: OMIM - KLF4

cMyc

The MYC protooncogene encodes a DNA-binding factor that can activate and repress transcription.
Ectopic expression of c-Myc can also cause tumorigenicity in offspring.

More recently shown that Oct4 together with either Klf4 or c-Myc is sufficient to generate iPS cells from neural stem cells.^[8]

Tbx3 transcription factor significantly improves the quality of iPS cells.^[9]

Links: OMIM - MYC

Generation of human melanocytes from induced pluripotent stem cells

PLoS One. 2011 Jan 13;6(1):e16182.

Ohta S, Imaizumi Y, Okada Y, Akamatsu W, Kuwahara R, Ohyama M, Amagai M, Matsuzaki Y, Yamanaka S, Okano H, Kawakami Y. Source Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan. Abstract Epidermal melanocytes play an important role in protecting the skin from UV rays, and their functional impairment results in pigment disorders. Additionally, melanomas are considered to arise from mutations that accumulate in melanocyte stem cells. The mechanisms underlying melanocyte differentiation and the defining characteristics of melanocyte stem cells in humans are, however, largely unknown. In the present study, we set out to generate melanocytes from human iPS cells in vitro, leading to a preliminary investigation of the mechanisms of human melanocyte differentiation. We generated iPS cell lines from human dermal fibroblasts using the Yamanaka factors (SOX2, OCT3/4, and KLF4, with or without c-MYC). These iPS cell lines were subsequently used to form embryoid bodies (EBs) and then differentiated into melanocytes via culture supplementation with Wnt3a, SCF, and ET-3. Seven weeks after inducing differentiation, pigmented cells expressing melanocyte markers such as MITF, tyrosinase, SILV, and TYRP1, were detected. Melanosomes were identified in these pigmented cells by electron microscopy, and global gene expression profiling of the pigmented cells showed a high similarity to that of human primary foreskin-derived melanocytes, suggesting the successful generation of melanocytes from iPS cells. This in vitro differentiation system should prove useful for understanding human melanocyte biology and revealing the mechanism of various pigment cell disorders, including melanoma.

^[10]

Thomson Factors

OCT4

Links: OMIM - OCT4

SOX2

Links: OMIM - SOX2

NANOG

Links: Nanog | OMIM - NANOG

LIN28

Links:

Target Genes

Oct4, Nanog, and Sox2 target genes

References

↑ Li L, Li Y, Sottas C, Culty M, Fan J, Hu Y, Cheung G, Chemes HE & Papadopoulos V. (2019). Directing differentiation of human induced pluripotent stem cells toward androgen-producing Leydig cells rather than adrenal cells. Proc. Natl. Acad. Sci. U.S.A. , 116, 23274-23283. PMID: 31591190 DOI.
↑ Ben-David U & Benvenisty N. (2011). The tumorigenicity of human embryonic and induced pluripotent stem cells. Nat. Rev. Cancer , 11, 268-77. PMID: 21390058 DOI.
↑ Zhao XY, Li W, Lv Z, Liu L, Tong M, Hai T, Hao J, Guo CL, Ma QW, Wang L, Zeng F & Zhou Q. (2009). iPS cells produce viable mice through tetraploid complementation. Nature , 461, 86-90. PMID: 19672241 DOI.
↑ Hamanaka S, Yamaguchi T, Kobayashi T, Kato-Itoh M, Yamazaki S, Sato H, Umino A, Wakiyama Y, Arai M, Sanbo M, Hirabayashi M & Nakauchi H. (2011). Generation of germline-competent rat induced pluripotent stem cells. PLoS ONE , 6, e22008. PMID: 21789202 DOI.
↑ Takahashi K & Yamanaka S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell , 126, 663-76. PMID: 16904174 DOI.
↑ Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K & Yamanaka S. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell , 131, 861-72. PMID: 18035408 DOI.
↑ Keramari M, Razavi J, Ingman KA, Patsch C, Edenhofer F, Ward CM & Kimber SJ. (2010). Sox2 is essential for formation of trophectoderm in the preimplantation embryo. PLoS ONE , 5, e13952. PMID: 21103067 DOI.
↑ Kim JB, Zaehres H, Wu G, Gentile L, Ko K, Sebastiano V, Araúzo-Bravo MJ, Ruau D, Han DW, Zenke M & Schöler HR. (2008). Pluripotent stem cells induced from adult neural stem cells by reprogramming with two factors. Nature , 454, 646-50. PMID: 18594515 DOI.
↑ Han J, Yuan P, Yang H, Zhang J, Soh BS, Li P, Lim SL, Cao S, Tay J, Orlov YL, Lufkin T, Ng HH, Tam WL & Lim B. (2010). Tbx3 improves the germ-line competency of induced pluripotent stem cells. Nature , 463, 1096-100. PMID: 20139965 DOI.
↑ Ohta S, Imaizumi Y, Okada Y, Akamatsu W, Kuwahara R, Ohyama M, Amagai M, Matsuzaki Y, Yamanaka S, Okano H & Kawakami Y. (2011). Generation of human melanocytes from induced pluripotent stem cells. PLoS ONE , 6, e16182. PMID: 21249204 DOI.

Reviews

Moraleda JM, Blanquer M, Bleda P, Iniesta P, Ruiz F, Bonilla S, Cabanes C, Tabares L & Martinez S. (2006). Adult stem cell therapy: dream or reality?. Transpl. Immunol. , 17, 74-7. PMID: 17157222 DOI.

Serafini M & Verfaillie CM. (2006). Pluripotency in adult stem cells: state of the art. Semin. Reprod. Med. , 24, 379-88. PMID: 17123233 DOI.

Pessina A & Gribaldo L. (2006). The key role of adult stem cells: therapeutic perspectives. Curr Med Res Opin , 22, 2287-300. PMID: 17076989 DOI.

Articles

Journal of Visualized Experiments - Generating iPS Cells from MEFS through Forced Expression of Sox-2, Oct-4, c-Myc, and Klf4

Hanna J, Saha K, Pando B, van Zon J, Lengner CJ, Creyghton MP, van Oudenaarden A & Jaenisch R. (2009). Direct cell reprogramming is a stochastic process amenable to acceleration. Nature , 462, 595-601. PMID: 19898493 DOI.

Ross JJ & Verfaillie CM. (2008). Evaluation of neural plasticity in adult stem cells. Philos. Trans. R. Soc. Lond., B, Biol. Sci. , 363, 199-205. PMID: 17282993 DOI.

Prentice DA & Tarne G. (2007). Treating diseases with adult stem cells. Science , 315, 328. PMID: 17234930 DOI.

Search PubMed

Search PubMed: Feb 2007 "adult stem cells" 811 reference articles of which 367 were reviews.

Search PubMed Now: adult stem cells | induced pluripotent stem cell |

Additional Images

Human induced pluripotent stem cells
Reprogramming MEF into ES-like cells
Reprogramming MEF into ES-like cells

External Links

External Links Notice - The dynamic nature of the internet may mean that some of these listed links may no longer function. If the link no longer works search the web with the link text or name. Links to any external commercial sites are provided for information purposes only and should never be considered an endorsement. UNSW Embryology is provided as an educational resource with no clinical information or commercial affiliation.

Center for iPS Cell Research and Application, Kyoto University Generation of Human induced Pluripotent Stem Cells PDF
Journal of Visualized Experiments - Generating iPS Cells from MEFS through Forced Expression of Sox-2, Oct-4, c-Myc, and Klf4
NIH Stem Cells - [http://stemcells.nih.gov/staticresources/info/scireport/PDFs/Chapter_10.pdf

Glossary Links

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Cite this page: Hill, M.A. (2023, December 11) Embryology Stem Cells - Induced. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Stem_Cells_-_Induced

What Links Here?

[PMID31591190-1] Li L, Li Y, Sottas C, Culty M, Fan J, Hu Y, Cheung G, Chemes HE & Papadopoulos V. (2019). Directing differentiation of human induced pluripotent stem cells toward androgen-producing Leydig cells rather than adrenal cells. Proc. Natl. Acad. Sci. U.S.A. , 116, 23274-23283. PMID: 31591190 DOI.

[PMID21390058-2] Ben-David U & Benvenisty N. (2011). The tumorigenicity of human embryonic and induced pluripotent stem cells. Nat. Rev. Cancer , 11, 268-77. PMID: 21390058 DOI.

[PMID19672241-3] Zhao XY, Li W, Lv Z, Liu L, Tong M, Hai T, Hao J, Guo CL, Ma QW, Wang L, Zeng F & Zhou Q. (2009). iPS cells produce viable mice through tetraploid complementation. Nature , 461, 86-90. PMID: 19672241 DOI.

[PMID21789202-4] Hamanaka S, Yamaguchi T, Kobayashi T, Kato-Itoh M, Yamazaki S, Sato H, Umino A, Wakiyama Y, Arai M, Sanbo M, Hirabayashi M & Nakauchi H. (2011). Generation of germline-competent rat induced pluripotent stem cells. PLoS ONE , 6, e22008. PMID: 21789202 DOI.

[PMID16904174-5] Takahashi K & Yamanaka S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell , 126, 663-76. PMID: 16904174 DOI.

[PMID18035408-6] Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K & Yamanaka S. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell , 131, 861-72. PMID: 18035408 DOI.

[PMID21103067-7] Keramari M, Razavi J, Ingman KA, Patsch C, Edenhofer F, Ward CM & Kimber SJ. (2010). Sox2 is essential for formation of trophectoderm in the preimplantation embryo. PLoS ONE , 5, e13952. PMID: 21103067 DOI.

[PMID18594515-8] Kim JB, Zaehres H, Wu G, Gentile L, Ko K, Sebastiano V, Araúzo-Bravo MJ, Ruau D, Han DW, Zenke M & Schöler HR. (2008). Pluripotent stem cells induced from adult neural stem cells by reprogramming with two factors. Nature , 454, 646-50. PMID: 18594515 DOI.

[PMID20139965-9] Han J, Yuan P, Yang H, Zhang J, Soh BS, Li P, Lim SL, Cao S, Tay J, Orlov YL, Lufkin T, Ng HH, Tam WL & Lim B. (2010). Tbx3 improves the germ-line competency of induced pluripotent stem cells. Nature , 463, 1096-100. PMID: 20139965 DOI.

[PMID21249204-10] Ohta S, Imaizumi Y, Okada Y, Akamatsu W, Kuwahara R, Ohyama M, Amagai M, Matsuzaki Y, Yamanaka S, Okano H & Kawakami Y. (2011). Generation of human melanocytes from induced pluripotent stem cells. PLoS ONE , 6, e16182. PMID: 21249204 DOI.

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