Fig. 32.1
Bone marrow- and adipose tissue-derived stem cells and hematopoietic stem cells in the cochlea. From bone marrow and adipose tissue, stromal or stem cells are available. They have a potential for forming in the stromal tissues in the cochlea. They can be a source of neural progenitors and express a marker for macrophages
BMSCs have gained particular attentions as a source of neuronal cells for transplantation (Fig. 32.1). Several methods for neural induction of BMSCs have been established [5–8]. Ogita and his colleague transplanted neurospheres derived from BMSCs into damaged cochleae and demonstrated the survival of BMSC-derived neurons in cochleae [9]. Kondo and her colleague established an induction method of BMSCs into sensory neuron phenotypes using Wnt1 [8]. They transplanted BMSCs into the cochlea followed by local application of neural induction medium and Wnt1, resulting in the survival of BMSC-derived neurons in the cochlea [8]. However, the hearing restoration by transplantation of BMSCs or BMSC-derived neural precursors has not been demonstrated unlike ES cell-derived neural cells [8, 9]. The capacity for neurite outgrowth and synaptogenesis could be key elements for functional restoration. The ability of BMSCs for differentiation into inner ear hair cells has also been reported [10, 11]. However, the efficient induction required Atho1 gene transfer. In 2010, the presence of multilineage-differentiating stress enduring (Muse) cell was discovered [12, 13]. Muse cells can be purified by FACS sorting with SSEA-3 and CD105 from mesenchymal stem cells including BMSCs. However, there has been no report on the potential of Muse cells for differentiation into inner ear lineages and for a source of transplants for the treatment of inner ears.
BMSCs have unique effects on modulation of immune responses [14–16], which is the focus of intensive investigations. BMSCs altered cell surface marker expression in T cells and decreased the expression of cytokines including interferon gamma and TNF-alpha. Several clinical trials, including large-scale placebo-controlled phase III clinical trials, are currently underway evaluating the therapeutic potential of BMSCs for the treatment of catastrophic inflammatory diseases, including steroid-refractory graft-versus-host disease, multiple sclerosis, and Crohn’s disease. Such a characteristic of BMSCs can be utilized for the promotion of transplanted cell survival. For successful cell therapy, the survival of sufficient numbers of transplants is included in key elements. Therefore, BMSCs may be used for suppression of immune response after cell transplantation into the inner ear.
32.2.2 Adipose Tissue-Derived Stem Cells
The adipose tissue is also a source of mesenchymal stem cells. In general, adipose tissue-derived stem or stromal cells (ADSCs) have the similar potential including neural differentiation and immune suppression to bone marrow-derived stem cells [17–19]. However, there are few publications on ADSCs for the treatment of the inner ear.
ADSCs have the capacity for secreting chemokine and growth factors similarly to BMSCs [18, 19]. Therefore, paracrine effects of ADSCs for the protection of hair cells were examined. ADSCs secreted several growth factors including hepatocyte growth factor (HGF) and insulin-like growth factor 1 [20], which are known to have protective effects on hair cells. Coculture of mouse cochlear explants with mouse ADSCs showed significant protection of cochlear hair cells against an aminoglycoside [20]. Interestingly, coculture with ADSCs showed superior protective effects to supplementation of HGF alone [20]. Therefore, combinations of several growth factors may have additive effects. At present, limited numbers of growth factors are available in clinical setting. From this point of view, ADSC transplantation can be an alternative for growth factor treatment.
32.3 Hematopoietic Stem Cells
Hematopoietic stem cell (HSC) transplantation was the first example of a successful stem cell therapy and is widely utilized for treating various diseases [22]. HSCs also consist of a heterogenous population of multipotent stem cells that collectively possess the potential to differentiate all blood cell types. HSCs can be purified from bone marrow cells by cell surface markers including Sca1 and c-Kit. HSC transplantation is commonly used in therapy for blood- or bone marrow-related malignancies.
In the field of inner ear biology, the presence of HSC-derived cells in the inner ear and their possible roles have been investigated (Fig. 32.1). Lang and colleague have demonstrated the presence of HSC-derived cells in the adult cochlea by analysis of murine HSC chimeras [23]. HSC-derived cells were most abundant in the spiral ligament. HSC-derived cells were also found in other locations normally occupied with fibrocytes and mesenchymal cells in the inner ear. Sato and colleague have demonstrated that the majority of HSC-derived cells in the cochlea are macrophages and that noise exposure induces accumulation of HSC-derived macrophages in the cochlea [24]. Okano and colleague have revealed that HSC-derived macrophages gradually turn over for several months during steady-state replacement by HSC-derived cells [25]. Not only in the cochlea but also in the vestibular peripherals HSC-derived cells are present, especially in the endolymphatic sac [26]. No spontaneous differentiation of HSCs into the hair cells, supporting cells, and neurons was identified in these studies. Therefore, HSCs are not candidates of a source for cell therapy, but play an important role in the immune systems of the inner ear.
References
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Sharif S, Nakagawa T, Ohno T, Matsumoto M, Kita T, Riazuddin S, et al. The potential use of bone marrow stromal cells for cochlear cell therapy. Neuroreport. 2007;18(4):351–4.PubMedCrossRef
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