**1. Introduction**

Stem cells present particular characteristics that make them different from other cell types. Firstly, they are unspecialized self-renewing tissue resident cells, and secondly they can be

© 2016 The Author(s). Licensee InTech. 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, provided the original work is properly cited. © 2018 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, provided the original work is properly cited.

induced to differentiate into a milieu of specialized cell types, thus holding promise for regenerative medicine. When these cells are isolated from adult fully differentiated tissues, they receive the attribute of adult stem cells, even though they are also present in infants and fetus. Therefore, it would be more appropriate to refer to them as tissue stem cells or mesenchymal stem cells to differentiate them from resident progenitors with limited differentiation capacity. MSCs can be isolated from a large number of tissues, such as bone marrow, adipose tissue, dental pulp, hair follicles, amniotic fluid, Wharton's jelly in the umbilical cord, and even from nervous or cardiac tissue. MSCs are multipotent and can be differentiated into chondrocytes, adipocytes, and osteoblasts under proper conditions [1, 2]. MSCs can be cloned and expanded *in vitro* more than a million fold without losing their differentiation potential [3] constituting, theoretically, a rich resource for tissue repair. However, their sensitivity to environmental cues and genetic factors together with a lack of standardized good manufacturing procedures (GMPs) using defined components has hampered their true therapeutic potential. Since the finding by Bartholomew et al. that MSCs inhibit mixed lymphocyte reactions and prevent the rejection of allogeneic skin grafts [4], a large number of reports have evidenced that MSCs are immunosuppressive and immunoregulatory, properties that can be harnessed therapeutically. However, challenges to fully understand and control MSC regenerative potential remain.

the loss of neural circuits. Later, in a subacute phase (2–4 days after injury), further ischemia occurs owing to ongoing edema, vessel thrombosis, and vasospasm. Persistent inflammatory cell infiltration causes further cell death and formation of very toxic cystic microcavities over time. Astrocytes, fibroblast, and pericytes proliferate and deposit extracellular matrix molecules into the perilesional area in the already intermediate and chronic phases, few weeks

Culturing Adult Stem Cells for Cell-Based Therapeutics: Neuroimmune Applications

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Spontaneous regeneration during and after having reached the chronic stage occurs due to the neuroplasticity capacity of the central nervous system (CNS); however, very limited gain of function is obtained decreasing advancing age, attributed to both extrinsic and intrinsic factors that modulate further onset, severity, and progression of the injury [12]. The cumulative myelin-associated protein anchorage to myelin sheet debris, in and around the epicenter of the injury, has a strong inhibitory nature. Nogo-A (reticulon-4 isoform A) and myelin-associated glycoprotein (MAG), among other myelin-associated proteins, bind to NOGO receptors to activate the GTPase Rho A, which activates Rho-associated protein kinase (ROCK), a regulator of further downstream effectors, leading to apoptosis and growth-cone collapse of regenerating axons involving neurite retraction [13–17]. Additional external barriers are potently adding to the inhibition of regeneration like the hypertrophic astrocytes and the reactive chemical scar with a number of axonal growth inhibitory chondroitin sulfate proteoglycans (CSPGs) [18].

The chronic SCI repair demands an intensive effort to overcome the impediments and enhance the intrinsic axon regeneration involving an efficient anatomical reorganization [19, 20]. Fortunately, although long distances for axonal reconnection or spared degenerated tracts are normally required, involving a long-term process (a rate of 1 mm/month for axon growth is estimated), it has been shown that as little as 10% of particular tracts can subserve substantial function [19, 20]. This in fact allows hypothesizing for a real recovery, mediated by bridging and partially reconnecting the spared axons allowing subsequent plasticity. Additionally, both, humans and rats, can regain a degree of function after incomplete injury, thought to be mostly due to local structural rearrangements, such as collateral sprouting from remaining axons in the gray matter, rather than by long-distance regeneration of axons in the white

Cell transplantation methods constitute a very promising strategy for SCI repair. Numerous studies with a diversity of cell types have clearly showed benefits to different extents, for

**Figure 1.** Summary of physiopathological events after SCI (a) and stem cell transplantation (b).

after SCI, when axons continue degenerating (**Figure 1a**) [11].

matter (**Figure 1b**) [21].

**2.2. Stem cell therapy for SCI repair**

In addition to MSC, the reprograming of terminally differentiated cells or induction of de-differentiation by the introduction of particular sets of transcription factors [5–7] opened an additional avenue of opportunities in the field of regenerative medicine. iPScs or induced pluripotent stem cells facilitate the production of patient-specific cells overcoming immune rejection and also ethical concerns. Although they have shown their value in the generation of *in vitro* models of human disease [8, 9], the low efficiency of reprogramming events and the safety concerns associated with the process of reprogramming has prevented their use in the clinic [6, 10].

Based on the research interests of our labs, this chapter, while reviewing the advances to generate clinical-grade stem cells or their by-products, highlights the potential benefits of stem cell-based therapeutics for the treatment of spinal cord injuries (SCI) and the neuroimmune disease myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
