Bone marrow mesenchymal stem cells are progenitors in vitro for inner ear hair cells

Abstract

Stem cells have been demonstrated in the inner ear but they do not spontaneously divide to replace damaged sensory cells. Mesenchymal stem cells (MSC) from bone marrow have been reported to differentiate into multiple lineages including neurons, and we therefore asked whether MSCs could generate sensory cells. Overexpression of the prosensory transcription factor, Math1, in sensory epithelial precursor cells induced expression of myosin VIIa, espin, Brn3c, p27Kip, and jagged2, indicating differentiation to inner ear sensory cells. Some of the cells displayed F-actin positive protrusions in the morphology characteristic of hair cell stereociliary bundles. Hair cell markers were also induced by culture of mouse MSC-derived cells in contact with embryonic chick inner ear cells, and this induction was not due to a cell fusion event, because the chick hair cells could be identified with a chick-specific antibody and chick and mouse antigens were never found in the same cell.Stem cells resident in bone marrow are the source of blood cells, but in addition to these hematopoietic stem cells, the bone marrow contains mesenchymal stem cells (MSCs) that can differentiate into cell types of all three embryonic germ layers (Colter et al., 2000;Doyonnas et al., 2004;Herzog et al., 2003;Hess et al., 2003;Jiang et al., 2002;Pittenger et al., 1999). This has been demonstrated in vivo in studies that track transplanted bone marrow cells to specific tissues where they differentiate into the resident tissue type (Mezey et al., 2003;Weimann et al., 2003). Differentiation may occur in part due to cell fusion (Wang et al., 2003;Weimann et al., 2003) in which the bone marrow cell takes on the identity of the peripheral cell. Recent studies have documented ex vivo differentiation of bone marrow derived stem cells into muscle cells (Doyonnas et al., 2004), cartilage (Pittenger et al., 1999), insulin-producing cells (Hess et al., 2003), and neurons (Dezawa et al., 2004;Hermann et al., 2004;Jiang et al., 2003;Kicic et al., 2003), both in vitro and after injection of these cells in vivo. Many of these cells have been used for transplantation and are a © 2006 Elsevier Inc. All rights reserved.Corresponding author: Albert Edge Eaton-Peabody Laboratory Massachusetts Eye and Ear Infirmary 243 Charles Street Boston, MA 02114 Tel: (617) 573-4452 Fax: (617) 720-4408 albert_edge@meei.harvard.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptMol Cell Neurosci. Author manuscript; available in PMC 2011 July 14. (Satoh and Fekete, 2005), and by the effect on hair ce...

Cells of adult brain germinal zone have properties akin to hair cells and can be used to replace inner ear sensory cells after damage

“…Cell replacement therapy is one potential way to repopulate damaged HCs. Pluripotent inner ear stem cells and transplanted exogenous progenitor cells have been verified as candidate cells (2,(6)(7)(8)39), but the controlled differentiation of stem cells into functional HCs is essential for hearing restoration.…”

“…However, the production of new HCs and SGNs is a rare event. Thus, considerable efforts have been made to identify a renewable cell source able to reconstruct damaged inner ears, with a special focus on various progenitor cells (2,(6)(7)(8), albeit limited success.…”

Can neurosphere production help restore inner ear transduction?

“…Cells with bona fide hair bundles have been generated in vitro from cell lines derived from embryonic chick ears (8). Stem cells derived from sources outside the inner ear such as embryonic stem cells (9), bone marrow mesenchymal stem cells (10), and adult mouse olfactory precursor cells (11) are also able to differentiate into cells that express hair cell markers. Moreover, neural stem cells have been transplanted into the inner ear and their survival and differentiation into sensory cells and/or neurons has been encouraging (12)(13)(14)(15), but practical application remains a challenge because yield is low and obstacles such as robust immune reactions and proper tissue integration have impeded progress.…”

Genetic and pharmacological intervention for treatment/prevention of hearing loss

“…Stefan Heller and colleagues have pursued the isolation and identification of intrinsic stem cells from the mouse vestibular sensory epithelium and investigated whether they can be used to repair the damaged cochlear nerve or organ of Corti (Li, Liu, & Heller, 2003). This group has also shown that mouse embryonic stem cells and mesenchymal stem cells from bone marrow can be coaxed down a hair cell pathway and will express a number of hair cell-specific genes in culture (Jeon, Oshima, Heller, & Edge, 2007;Li, Roblin, Liu, & Heller, 2003;Oshima et al, 2007). They have also shown that neural progenitors derived from mouse embryonic stem cells can integrate into a damaged cochlear nerve and send out neural processes toward the cochlea (Corrales et al, 2006).…”