**4. miRNA regulation of MSC immunomodulatory capacity**

Micro-RNAs (miRNAs) constitute a class of single-stranded non-coding RNAs of approximately 18–22 nucleotides that function as endogenous regulators of gene expression through the degradation of the target mRNA or the inhibition of the transcription process. Over the last decade, the growing interest for miRNA applications elucidated their involvement into many biological mechanisms, like cell growth and proliferation. Based on the observation that miRNAs are differentially regulated in the presence of pathological conditions like cancer or immune diseases, many researchers have proposed their use as diagnostic markers or therapeutic targets. Several studies revealed the miRNA involvement into the hematopoietic stem cell (HSC) system, driving aspects like cell survival, self-renewal and differentiation. Moreover, these 'immuno-miRs' orchestrate crucial steps of both innate and adaptive immune cell development and function [41]. miR-21, miR-146a and miR-155 are included in this category and are induced upon T-cell receptor (TCR)

**131**

**5. Conclusions**

**Author details**

of Bologna, Bologna, Italy

provided the original work is properly cited.

Carmen Ciavarella\* and Gianandrea Pasquinelli

\*Address all correspondence to: carmen.ciavarella2@unibo.it

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Medicine, (DIMES)-University of Bologna, S. Orsola-Malpighi University Hospital

Clinical Pathology, Department of Experimental, Diagnostic and Specialty

The regenerative and reparative properties of MSCs are certainly undisguised even though many efforts are necessary to ensure their use for clinical therapy. The contradictory inflammatory activity of MSCs is a result of their plastic nature and represents a critical issue that needs to be addressed. Tissue-resident MSCs can represent the optimal target of stem cell-reprogramming therapies aimed at restoring their native reparative properties. The emerging role of miRNAs in regulating the MSC functions is promising and requires further investigations for miRNA manipulation in order to address MSC towards a more efficient and safe reparative activity.

*The Dual Nature of Mesenchymal Stem Cells (MSCs): Yin and Yang of the Inflammatory Process*

activation through the NF-kB cascade. miRNAs have also been shown to regulate the stem cell behaviour, self-renewal and differentiation; therefore, investigating immuno-miRs in human MSCs could be suggestive of their reparative properties like differentiation and immunomodulatory potency. Some of the described immuno-miRs target the TLR pathway in MSCs or immune cells suppressing or enhancing TLR activation by targeting adapter molecules, cytokines and transcription factors. At this regard, a work by Matysiak et al. demonstrated the upregulation of several miRNAs in differentiated BMSCs that had lost immunomodulation, including miR-146a, together with a low expression of PGE2 [42]. The role of miR-155 in interfering with MSC immunomodulation has been also reported; indeed, miR-155 decreases the iNOS production in cytokine-activated MSCs, partially targeting TGF-beta-activated kinase 2 (TAB2), an adapter protein involved in TLR pathways [43]. As recently demonstrated, many of the therapeutic effects of MSCs are mediated by the extracellular vesicles (EVs), which are membrane-bound vesicles that serve as vehicle of mRNAs and proteins. Moreover, EVs are enriched of miRNAs that are released in the circulatory system. The EV-released miRNAs, such as Let-7b, miR-1180 and miR-183, induce macrophage polarization into M2 phenotype and mitigate inflammation by reducing TLR4 [44]. The mechanisms regulating the miRNA-MSCs interplay are complex and require further investigations; the use of miRNA-enriched EVs derived from human MSCs could be the promising therapeutic cell-free alternative for the cure of GvHD and inflammatory diseases.

*DOI: http://dx.doi.org/10.5772/intechopen.82877*

*The Dual Nature of Mesenchymal Stem Cells (MSCs): Yin and Yang of the Inflammatory Process DOI: http://dx.doi.org/10.5772/intechopen.82877*

activation through the NF-kB cascade. miRNAs have also been shown to regulate the stem cell behaviour, self-renewal and differentiation; therefore, investigating immuno-miRs in human MSCs could be suggestive of their reparative properties like differentiation and immunomodulatory potency. Some of the described immuno-miRs target the TLR pathway in MSCs or immune cells suppressing or enhancing TLR activation by targeting adapter molecules, cytokines and transcription factors. At this regard, a work by Matysiak et al. demonstrated the upregulation of several miRNAs in differentiated BMSCs that had lost immunomodulation, including miR-146a, together with a low expression of PGE2 [42]. The role of miR-155 in interfering with MSC immunomodulation has been also reported; indeed, miR-155 decreases the iNOS production in cytokine-activated MSCs, partially targeting TGF-beta-activated kinase 2 (TAB2), an adapter protein involved in TLR pathways [43]. As recently demonstrated, many of the therapeutic effects of MSCs are mediated by the extracellular vesicles (EVs), which are membrane-bound vesicles that serve as vehicle of mRNAs and proteins. Moreover, EVs are enriched of miRNAs that are released in the circulatory system. The EV-released miRNAs, such as Let-7b, miR-1180 and miR-183, induce macrophage polarization into M2 phenotype and mitigate inflammation by reducing TLR4 [44]. The mechanisms regulating the miRNA-MSCs interplay are complex and require further investigations; the use of miRNA-enriched EVs derived from human MSCs could be the promising therapeutic cell-free alternative for the cure of GvHD and inflammatory diseases.

### **5. Conclusions**

*Update on Mesenchymal and Induced Pluripotent Stem Cells*

and represents the early stage during calcification process [40]. AAA-MSCs also exhibited a marked osteogenic ability, correlating with the vascular calcium levels as measured by angio-CT in the enrolled patients [37]. Thus, it can be postulated that MSCs are key players during the renewal as well as the pathological conditions affecting the vascular wall. The MSC behaviour can be seen as fine balance between two opposite forces, which is strongly influenced by the external microenvironment and the interaction with the neighboring cells. At this regard, the immune cells and the cytokines released during inflammation are key factors in exacerbating the

*Phenotypic and functional characteristics of healthy versus pathological vascular MSCs.*

The most remarkable characteristics of AAA-MSCs and their comparison to the

Micro-RNAs (miRNAs) constitute a class of single-stranded non-coding RNAs

of approximately 18–22 nucleotides that function as endogenous regulators of gene expression through the degradation of the target mRNA or the inhibition of the transcription process. Over the last decade, the growing interest for miRNA applications elucidated their involvement into many biological mechanisms, like cell growth and proliferation. Based on the observation that miRNAs are differentially regulated in the presence of pathological conditions like cancer or immune diseases, many researchers have proposed their use as diagnostic markers or therapeutic targets. Several studies revealed the miRNA involvement into the hematopoietic stem cell (HSC) system, driving aspects like cell survival, self-renewal and differentiation. Moreover, these 'immuno-miRs' orchestrate crucial steps of both innate and adaptive immune cell development and function [41]. miR-21, miR-146a and miR-155 are included in this category and are induced upon T-cell receptor (TCR)

osteogenic differentiation of healthy VW-MSCs [37].

**4. miRNA regulation of MSC immunomodulatory capacity**

hVW-MSCs are summarized in **Table 1**.

**130**

**Table 1.**

The regenerative and reparative properties of MSCs are certainly undisguised even though many efforts are necessary to ensure their use for clinical therapy. The contradictory inflammatory activity of MSCs is a result of their plastic nature and represents a critical issue that needs to be addressed. Tissue-resident MSCs can represent the optimal target of stem cell-reprogramming therapies aimed at restoring their native reparative properties. The emerging role of miRNAs in regulating the MSC functions is promising and requires further investigations for miRNA manipulation in order to address MSC towards a more efficient and safe reparative activity.
