**8. Future conclusions and addresses**

**7. Cancer stem cells (CSC); exosomes**

198 Stromal Cells - Structure, Function, and Therapeutic Implications

of epithelial to mesenchymal transmission [71].

of extrinsic microenvironmental factors [72].

ment, which are:

Malignant tumors arise from a small subset of cancer cells, have tumor heterogeneity, and small populations of cells with characteristics equivalent to SCs. These cells, called cancer stem cells (CSC) or cancer-initiating cells (CIC), have been identified in many malignancies and are thought to form the tumor clonogenic nucleus. The CSCs share many characteristics of ES and show activation of one or more signal transduction pathways, which are involved in tissue homeostasis and development, including Notch, Hedgehog (Hh), and Wnt pathways. Notch signaling, similar to the Wnt and Hh pathways, is a pathway for determining the fate of the evolutionarily conserved primordial cell, with great relevance in the biology of cancer, from CSC to angiogenesis and tumor immunity. The CSCs generally have slow growth rates and are resistant to chemotherapy and/or radiation therapy. The new treatment strategies seek to control the replication, survival, and differentiation of the CSCs [70]. These cells originate from a more differentiated cancer cell, with self-renewing properties, probably as a result

The most important and useful property of the CSC is that of self-renewal and characteristic differentiation, which is considered as a one-way specialization process as the cells develop the functions of their final destination and lose their immature characteristics, such as selfrenewal. This property shows parallels between SCs and cancer cells. The tumors originate by the transformation of normal SCs by means of similar signaling routes, to which they regulate self-renewal, both of SCs and CSCs; the latter include the undefined potential of self-renewal that starts tumorigenesis. Otherwise, CSCs could be derived from a SC of normal tissue that undergoes a transformation as a result of oncogenic somatic mutations, due to the influence

The CSCs are associated with tumor onset, metastasis, progression, invasion, recurrence, and resistance to therapies, and they play a central role in the biology of cancer cells; they interact with their surrounding cells inducing angiogenesis and metastasis. In the tumor microenvironment, multiple types of cells coexist, including adult SCs, CSCs, and stromal cells, and communicate with each other in modulating, tumor progression, functionally release exosomes that can be absorbed by CSCs or adult SCs, and modify their phenotype. Recent studies show that exosomes participate in interactions between cells within the tumor microenviron-

We take Hannafon's approach in questions related to the function of the exosomes involved in the interaction of CSCs, adult SCs, and the surrounding cells within the tumor microenviron-

Do CSCs or adult SCs secrete exosomes that affect the function of the stromal cell? Are CSCs or adult SCs modified by the exosomes released from CSCs and surrounding stromal cells? What are the possible molecular mechanisms and the biological consequences of exosomemediated interactions between CSCs, adult SCs, and the cells that surround them? [74].

The SCs secrete a large number of exosomes, and in the extracellular environment, they function as intercommunicators in the tumor microenvironment and actively in tumorigenesis,

ment by means of exosomal signals, modulating tumor progression [73].

Due to its complexity, the research and application of cell therapy with cells and cellular products should be considered with a multidisciplinary and translational approach and represents a great therapeutic potential for refractory diseases to conventional treatments such as noncommunicable chronic diseases: diabetes, cardiovascular ischemic diseases, cerebrovascular or renal diseases, degenerative diseases such as cancer, neurodegenerative such as Alzheimer's disease, multiple sclerosis, and aging.

Thus, cell therapy with MSCs emerges as a promising therapeutic tool, the main therapeutic objective of which is healing through trans-differentiation to repair and replace damaged cells and generate new healthy cells. The rapid progress in MSC research and the primary function in cellular niches under normal and pathological physiological conditions and the management of cellular intercommunication of the microenvironment through the paracrine secretion and their biological products are being incorporated into clinical practice.

**Author details**

Daniel Ascencio González1

Salvador Zubirán, Mexico City, Mexico

5 Hospital ABC, Mexico City, Mexico

4 Hospital Angeles Mexico, Mexico City, Mexico

2010;**3**(5):547-558. DOI: 10.1007/s12265-010-9171-0

Ciba Foundation Symposium. 1988;**136**:42-60

DOI: 10.1016/j.stem.2012.02.005

DOI: 10.1098/rstb.2009.0149

Cinvestav, Mexico City, Mexico

Sergio Ayala Fraustro4

Mexico City, Mexico

**References**

cr.2010.44

\*, Rogelio Hernández Pando<sup>2</sup>

1 Facultad Mexicana de Medicina, Hospital Angeles del Pedregal, La Salle University,

2 Experimental Pathology Unit, Instituto Nacional De Ciencias Médicas y Nutrición

3 Center for Research and Advanced Studies of the National Polytechnic Institute,

[1] Singer NG, Caplan AI. Mesenchymal stem cells: Mechanisms of inflammation. Annual Review of Pathology. 2011;**6**:457-478. DOI: 10.1146/annurev-pathol-011110-130230

[2] Shi Y, Hu G, Su J, Li W, Chen Q, et al. Mesenchymal stem cells: A new strategy for immunosuppression and tissue repair. Cell Research. 2010;**20**(5):510-518. DOI: 10.1038/

[3] Nguyen BK, Maltais S, Perrault LP, Tanguay JF, Tardif JC, et al. Improved function and myocardial repair of infarcted heart by intracoronary injection of mesenchymal stem cell-derived growth factors. Journal of Cardiovascular Translational Research.

[4] Ranganath SH, Levy O, Inamdar MS, Karp JM. Harnessing the mesenchymal stem cell secretome for the treatment of cardiovascular disease. Cell Stem Cell. 2012;**10**(3):244-258.

[5] Watt FM, Driskell RR. The therapeutic potential of stem cells. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 2010;**365**(1537):155-163.

[6] Lajtha LG. Stem cell concepts. Nouvelle Revue Française d'Hématologie. 1979;**21**(1):59-65 [7] Owen M, Friedenstein AJ. Stromal stem cells: Marrow-derived osteogenic precursors.

and Aaron Torres Garcia<sup>5</sup>

\*Address all correspondence to: danielascencio@gmail.com

, Miguel Ángel Gómez Lim3

Therapeutic Strategies of Secretome of Mesenchymal Stem Cell

http://dx.doi.org/10.5772/intechopen.78092

,

201

The initial paradigm of cellular therapy for tissue and organ repair and regeneration has been modified, with new knowledge from experimental, preclinical, and clinical studies related to the mechanism of action of MSCs both *in vivo* and *in vitro*, which have demonstrated to be processes fundamentally of paracrine action, by means of the generation of exosomes, microvesicles, and the horizontal transfer of proteins, mRNA, and microRNA.

Recently, a group of secreted vesicles, the "exosome", has been identified as the main mediator of the therapeutic efficacy of MSC. The ExMV participate in intercellular, local, and remote communication, which are translated into pleiotropic actions and generate a therapeutic potential by transferring biologically active molecules and which can be used as new biomarkers and potential regulators of inflammation and immune response to detect immune rejections. Exosome/microvesicle therapy derived from MSCs has potential advantages. First, it prevents the transfer of cells that may have mutated or damaged DNA. Second, the vesicles are small and easily circulated, while the MSCs are too large to easily circulate through the capillaries and many do not even reach the first capillary bed. Third, the dose of MSC decreases rapidly after transplantation, but the administration of the biological products of the cells allows higher therapeutic "doses". The disadvantage of using vesicles derived from MSCs is that they are static and cannot occur more when they are transplanted. The therapeutic efficacy of MSCs is based on their ability to respond in the microenvironment of the lesion, whereas the isolated exosomes are not expected to do so. The opportunity to exploit the potential therapy of MSCs and their products opens new scenarios for the identification of new molecules for the repair and regeneration of organs and tissues through proteome analysis of the secretome.

In the short term, the exosomes derived from MSCs will progress to clinical studies, and their usefulness and effectiveness will depend on establishing a series of critical parameters such as standardizing reproducible production methods for the manufacture of exosomes/microvesicles with precisely defined content, standardizing storage methods that maintain their potency, and evaluating therapeutic efficacy in controlled clinical trials, of appropriate power, designed with written criteria and with solid research foundations to generate scientific results that allow the translation of basic knowledge to create new regenerative therapies.
