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Novel Therapeutic Approaches in Regenerative Medicine—Adult Tissue-Derived Very Small Embryonic-like Stem Cells and Harnessing Paracrine Signals of Adult 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))

Abstract

The regenerative medicine is searching for proper stem cells that could be employed for therapy to regenerate damaged solid organs (e.g., heart, Brain, or liver). It is striking that, for a variety of adult tissue-derived cells currently employed in experimental animal and clinical models (e.g., bone marrow or mobilized peripheral blood-derived CD34+ or CD133+ stem cells, mesenchymal stem cells), the observed final outcomes are often similar. This fact and the lack of convincing documentation for significant donor-recipient chimerism in organs (e.g., heart, liver, brain) in most of the patients treated with adult stem cells indicates that a mechanism other than transdifferentiation of stem cells infused systemically into peripheral blood or injected directly into damaged organs may play an important role in those cases where an obvious beneficial effect of stem cell therapy is observed. In this review, we will discuss the potential contribution of rare pluripotent/multipotent stem cells present in cell preparations (e.g., bone marrow, umbilical cord blood, mobilized peripheral blood) as well as a paracrine role of growth factors, cytokines, chemokines, bioactive lipids, and microvesicles (MVs) released from adult cells employed as cellular therapeutics in regenerative medicine.

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Authors and Affiliations

  1. Stem Cell Institute, James Graham Brown Cancer Center, University of Louisville, 500 South Floyd Street, Rm. 107, 40202, Louisville, KY, USA

    Magda Kucia, Malwina Suszynska, Janina Ratajczak & Mariusz Z. Ratajczak MD, PhD

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  1. Magda Kucia
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  2. Malwina Suszynska
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  3. Janina Ratajczak
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  4. Mariusz Z. Ratajczak MD, PhD
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Correspondence to Mariusz Z. Ratajczak MD, 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

Current therapeutic strategies in regenerative medicine employing adult stem cells for damaged solid organs are mainly based on utilization of their paracrine effects by secreted soluble factors and MVs [72, 73, 75, 76]. Overall, paracrine effects and MV-based therapies also open up new possibilities for clinical applications of iPSCs. Since in vivo application of iPSCs is limited by the high risk of teratoma formation by these cells, MVs from patient-derived iPSCs could be employed as a novel generation of therapeutics to rescue damaged organs and tissues. Based on this possibility, we envision that patient-derived iPSCs could be employed as MV-producing cells. Moreover, taking advantage of the recently proposed epigenetic memory of cells employed for generation of iPSCs [77], one can also envision that, for example, MVs from keratinocyte-derived iPSCs would be preferentially enriched for mRNA and miRNA for epidermis stem cells and thus affect regeneration of damaged skin (e.g., after burns), or similarly MVs isolated from supernatants of cardiomyocyte-derived iPSCs would have by similar mechanisms advantages in regeneration of damaged myocardium.

However, beside paracrine effects of more differentiated adult stem/progenitor cells it is also a hope for clinical application of pluripotent/multipotent isolated from the adult tissues and new data from our group [26, 44, 45] and other groups [28, 47, 49] has provided more evidence on the existence of primitive embryonic-like stem cells in murine adult tissues and their potential role in (1) tissue organ rejuvenation, (2) longevity, and (3) regeneration/repair of damaged tissues. Nevertheless, while murine BM-derived VSELs have been extensively characterized, we are aware that more work is needed to better characterize small CD133 + Lin− CD45− cells at the molecular level in humans. We need to determine whether human VSELs have the same molecular signature (e.g., an open chromatin structure at the Oct4 promoter, modification of somatic imprinting, and the presence of bivalent domains) as their murine counterparts. If we can confirm that a similar imprinting-related mechanism operates for human VSELs, perhaps a controlled modulation of the somatic imprinted state to produce proper de novo methylation of somatic imprinted genes on the maternal and paternal chromosomes could increase the regenerative power of these cells [39] and lead to their broader application in the clinic. Of note, recently National Institutes of Health (NIH) sponsored a first clinical trial to employ human BM-derived VSELs for treatment of periodontitis lesions in patients [http://www.neostem.com/news/vsel1mgrant.html].

Acknowledgments

This work was supported by NIH grant 2R01 DK074720, the Stella and Henry Endowment and grant Maestro 2011/02/A/NZ4/00035 to MZR.

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Kucia, M., Suszynska, M., Ratajczak, J., Ratajczak, M. (2014). Novel Therapeutic Approaches in Regenerative Medicine—Adult Tissue-Derived Very Small Embryonic-like Stem Cells and Harnessing Paracrine Signals of Adult 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_2

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