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Molecular Signature of Very Small Embryonic-like Stem Cells

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Adult Stem Cell Therapies: Alternatives to Plasticity

Part of the book series: Stem Cell Biology and Regenerative Medicine ((STEMCELL))

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Abstract

Tissue and organ rejuvenation and senescence/aging are closely related to the function of stem cells. Thus, stem cells have been considered as guardians for the homeostasis of tissue/organ throughout life span. Recently, we identified a population of pluripotent Oct4+  very small embryonic/epiblast-like stem cells (VSELs) residing in the adult murine bone marrow (BM) and human cord blood (CB). VSELs can differentiate into cells from all three germ layers in vitro culture condition and in vivo tissue regeneration animal models. VSELs express the gene-expression and epigenetic profiling, which are similar to germ-line stem cells including (i) open/active chromatin structure in Oct4 promoter, (ii) parent-of-origin-specific reprogramming of genomic imprinting, (iii) deoxyribonucleic acid (DNA) demethylation in the promoter of germ-line lineage genes, and (iv) reactivate the X chromosome (in female pluripotent stem cells, PSCs). The unique epigenetic reprogramming in VSELs suggest that they could developmentally originate from the migratory primordial germ cells (PGCs) and the proliferation of VSELs are negatively controlled by epigenetic changes of some imprinted genes that regulate insulin/insulin-like growth-factor (Ins/Igf) signaling (Igf2, H19, Igf2R, and Rasgrf1). Since the chronic exposure to Ins/Igf signaling negatively correlates with longevity, we propose that Ins/Igf signaling mediated decrease in the number of VSELs could be a novel explanation of ageing. Therefore, VSELs could play a pivotal role in maintaining the integrity of adult tissues and these cells could provide a therapeutic alternative to stem cells isolated from embryos. Therefore, the understanding the precise molecular signature of VSELs such as reprogrammed genomic imprints could increase the regenerative power of these cells.

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Authors and Affiliations

  1. Department of Biomedical Sciences, Department of Physiology, University of Ulsan College of Medicine, Pungnap-2 dong, Songpa-gu, 138-736, Seoul, Korea

    Hyunsook Kang, Jisun Lim, Jinbeom Heo, Jaeho Jeong, YongHwan Kim & Dong-Myung Shin PhD

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  1. Hyunsook Kang
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  2. Jisun Lim
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  3. Jinbeom Heo
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  4. Jaeho Jeong
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  6. Dong-Myung Shin PhD
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Correspondence to Dong-Myung Shin PhD .

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  1. University of Louisville, Stem Cell Institute, James Graham Brown Cancer Center, Louisville, Kentucky, USA

    Mariusz Z. Ratajczak

Conclusions

Conclusions

Several attempts have been made in the past few years to purify a population of PSCs from adult tissues. The very primitive VSELs in adult tissues could function as precursor for monopotent TCSCs. It is very likely that these cells play a physiological role in rejuvenation of a pool of TCSCs under steady state conditions. Molecular signature of VSELs demonstrates that they VSELs exhibit the common features for pluripotency, (i) open chromatin structure in the promoters of PSC-specific TFs (Oct4 and Nanog), (ii) BD domain in the promoters of developmental master regulator TFs, and (iii) partial reactivation of Xi. As respect to gene expression and epigenetic programs of germ-line markers, VSELs share several molecular signatures with epiblast and migrating PGCs, suggesting that VSELs developmentally originate from epiblast-derived migrating PGCs. Based on the similarity to PGCs, the capacity for proliferation and differentiation of VSELs is orchestrated by DNA methylation status of some of the developmentally crucial imprinted genes (e.g., H19, Igf2, Igf2R, p57KIP2, and Rasgrf1). The progress loss of the proliferation-repressive epigenetic marks in VSELs results in the increased sensitivity to Ins/Igf signaling and concomitantly depletion of primitive VSELs population during ageing process. VSELs could function as a reserve pool of primitive stem by regeneration into several tissue residing TCSCs (e.g., MSCs, HSCs, cardiac SCs) in response to tissue/organ injury. Thus, VSELs isolated from adult tissues are safe and ethically noncontroversial source of SCs as an alternative to embryonic types of PSCs for regenerative medicine. To successfully employ VSELs in the realm of regenerative medicine, it is very important to establish experimental protocols for unleashing the regenerative potential of VSELs like reprogramming of their growth repressive genomic imprints status into regular somatic pattern and the study about precise molecular signature of VSELs could advance the development of ex vivo expansion protocol for these SCs.

Conflicts Of Interest Statement

The authors declare that they have no competing financial interests.

Acknowledgments

This work was supported by a grant from the Asian Institute for Life Sciences, Seoul, Korea (2014–528) and a grant from the Korean Health Technology R & D Project, Ministry of Health & Welfare, Republic of Korea (A120301) to DMS.

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Kang, H., Lim, J., Heo, J., Jeong, J., Kim, Y., Shin, DM. (2014). Molecular Signature of Very Small Embryonic-like Stem Cells. In: Ratajczak, M. (eds) Adult Stem Cell Therapies: Alternatives to Plasticity. Stem Cell Biology and Regenerative Medicine. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-1001-4_12

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