The human nose harbors a niche of olfactory ectomesenchymal stem cells displaying neurogenic and osteogenic properties.

We previously identified multipotent stem cells within the lamina propria of the human olfactory mucosa, located in the nasal cavity. We also demonstrated that this cell type differentiates into neural cells and improves locomotor behavior after transplantation in a rat model of Parkinson's disease. Yet, next to nothing is known about their specific stemness characteristics. We therefore devised a study aiming to compare olfactory lamina propria stem cells from 4 individuals to bone marrow mesenchymal stem cells from 4 age- and gender-matched individuals. Using pangenomic microarrays and immunostaining with 34 cell surface marker antibodies, we show here that olfactory stem cells are closely related to bone marrow stem cells. However, olfactory stem cells also exhibit singular traits. By means of techniques such as proliferation assay, cDNA microarrays, RT-PCR, in vitro and in vivo differentiation, we report that when compared to bone marrow stem cells, olfactory stem cells display (1) a high proliferation rate; (2) a propensity to differentiate into osseous cells; and (3) a disinclination to give rise to chondrocytes and adipocytes. Since peripheral olfactory stem cells originate from a neural crest-derived tissue and, as shown here, exhibit an increased expression of neural cell-related genes, we propose to name them olfactory ectomesenchymal stem cells (OE-MSC). Further studies are now required to corroborate the therapeutic potential of OE-MSCs in animal models of bone and brain diseases.

[1]  A. Mackay-Sim,et al.  Olfactory stem cells can be induced to express chondrogenic phenotype in a rat intervertebral disc injury model. , 2009, The spine journal : official journal of the North American Spine Society.

[2]  E. Dupin,et al.  High frequency of cephalic neural crest cells shows coexistence of neurogenic, melanogenic, and osteogenic differentiation capacities , 2009, Proceedings of the National Academy of Sciences.

[3]  E. Wolvetang,et al.  Adipocyte differentiation in human embryonic stem cells transduced with Oct4 shRNA lentivirus. , 2009, Stem cells and development.

[4]  Andreas Radbruch,et al.  SiPaGene: A new repository for instant online retrieval, sharing and meta-analyses of GeneChip® expression data , 2009, BMC Genomics.

[5]  G. Atkins,et al.  The skeleton as an intracrine organ for vitamin D metabolism. , 2008, Molecular aspects of medicine.

[6]  W. Farrar,et al.  Cancer stem cells, CD200 and immunoevasion. , 2008, Trends in immunology.

[7]  E. Kang,et al.  LPIN1 genetic variation is associated with rosiglitazone response in type 2 diabetic patients. , 2008, Molecular genetics and metabolism.

[8]  P. Silburn,et al.  Olfactory Mucosa Is a Potential Source for Autologous Stem Cell Therapy for Parkinson's Disease , 2008, Stem cells.

[9]  D. Guilloteau,et al.  Partial recovery of dopaminergic pathway after graft of adult mesenchymal stem cells in a rat model of Parkinson's disease , 2008, Neurochemistry International.

[10]  E. Dupin,et al.  The stem cells of the neural crest , 2008, Cell cycle.

[11]  J. Ringe,et al.  Specific plasma membrane protein phenotype of culture-amplified and native human bone marrow mesenchymal stem cells. , 2008, Blood.

[12]  S. Lehmann,et al.  Functional, molecular and proteomic characterisation of bone marrow mesenchymal stem cells in rheumatoid arthritis , 2007, Annals of the rheumatic diseases.

[13]  L. Sensébé Clinical grade production of mesenchymal stem cells. , 2008, Bio-medical materials and engineering.

[14]  J. L. Hansen,et al.  S100A4: a common mediator of epithelial–mesenchymal transition, fibrosis and regeneration in diseases? , 2008, Journal of molecular medicine.

[15]  Masayuki Yamamoto,et al.  Regulation of adipocyte differentiation of bone marrow stromal cells by transcription factor GATA-2. , 2007, Biochemical and biophysical research communications.

[16]  A. Amano,et al.  Zinc‐Finger Transcription Factor Odd‐Skipped Related 2 Is One of the Regulators in Osteoblast Proliferation and Bone Formation , 2007, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[17]  Hyunjin Cho,et al.  Role of CD9 in proliferation and proangiogenic action of human adipose-derived mesenchymal stem cells , 2007, Pflügers Archiv - European Journal of Physiology.

[18]  S. Nishikawa,et al.  Neuroepithelial Cells Supply an Initial Transient Wave of MSC Differentiation , 2007, Cell.

[19]  G. Daculsi,et al.  Interactions of total bone marrow cells with increasing quantities of macroporous calcium phosphate ceramic granules , 2007, Journal of materials science. Materials in medicine.

[20]  Elizabeth Gould,et al.  How widespread is adult neurogenesis in mammals? , 2007, Nature Reviews Neuroscience.

[21]  R. Reed,et al.  Contribution of olfactory neural stem cells to tissue maintenance and regeneration , 2007, Nature Neuroscience.

[22]  F. Roisen,et al.  Human adult olfactory neural progenitors promote axotomized rubrospinal tract axonal reinnervation and locomotor recovery , 2007, Neurobiology of Disease.

[23]  Claes Nordborg,et al.  Human Neuroblasts Migrate to the Olfactory Bulb via a Lateral Ventricular Extension , 2007, Science.

[24]  S. Oleskevich,et al.  Differentiation of Adult Mouse Olfactory Precursor Cells into Hair Cells In Vitro , 2007, Stem cells.

[25]  P. Charbord,et al.  Culture and characterization of human bone marrow mesenchymal stem cells. , 2007, Methods in molecular medicine.

[26]  M. Salto‐Tellez,et al.  Establishing Clonal Cell Lines with Endothelial-Like Potential from CD9hi, SSEA-1− Cells in Embryonic Stem Cell-Derived Embryoid Bodies , 2006, PloS one.

[27]  Y. Kawakami,et al.  The role of TGFβs and Sox9 during limb chondrogenesis , 2006 .

[28]  H. Ryoo,et al.  Tetraspanin CD9 regulates osteoclastogenesis via regulation of p44/42 MAPK activity. , 2006, Biochemical and biophysical research communications.

[29]  Andrew D Rowan,et al.  The Mammalian Chitinase-like Lectin, YKL-40, Binds Specifically to Type I Collagen and Modulates the Rate of Type I Collagen Fibril Formation* , 2006, Journal of Biological Chemistry.

[30]  P. Charbord,et al.  The concept of mesenchymal stem cells. , 2006, Regenerative medicine.

[31]  M. Xiao,et al.  The therapeutic potential of human olfactory-derived stem cells. , 2006, Histology and histopathology.

[32]  W. Löscher,et al.  Neurogenesis in the adult rat piriform cortex , 2006, Neuroreport.

[33]  N. Nardi,et al.  Mesenchymal stem cells: isolation, in vitro expansion and characterization. , 2006 .

[34]  A. Nowitzke,et al.  Autologous olfactory ensheathing cell transplantation in human spinal cord injury. , 2005, Brain : a journal of neurology.

[35]  Human adult olfactory neural progenitors rescue axotomized rodent rubrospinal neurons and promote functional recovery , 2005, Experimental Neurology.

[36]  A. Mackay-Sim,et al.  Multipotent stem cells from adult olfactory mucosa , 2005, Developmental dynamics : an official publication of the American Association of Anatomists.

[37]  N. Cooper,et al.  Human adult olfactory neuroepithelial derived progenitors retain telomerase activity and lack apoptotic activity , 2005, Brain Research.

[38]  M. Mushipe,et al.  Effects of Pleiotrophin (PTN) Over-expression on Mouse Long Bone Development, Fracture Healing and Bone repair , 2005, Calcified Tissue International.

[39]  M. Qiu,et al.  Induction of Oligodendrocytes From Adult Human Olfactory Epithelial‐Derived Progenitors by Transcription Factors , 2005, Stem cells.

[40]  F. Roisen,et al.  Endoscopic Biopsy of Human Olfactory Epithelium as a Source of Progenitor Cells , 2005, American journal of rhinology.

[41]  K. Whitlock A New Model for Olfactory Placode Development , 2004, Brain, Behavior and Evolution.

[42]  André Parent,et al.  Evidence of newly generated neurons in the human olfactory bulb. , 2004, Brain research. Developmental brain research.

[43]  J. MacDonald,et al.  Olfactory Horizontal Basal Cells Demonstrate a Conserved Multipotent Progenitor Phenotype , 2004, The Journal of Neuroscience.

[44]  V. Gallo,et al.  NG2-expressing cells in the subventricular zone are type C–like cells and contribute to interneuron generation in the postnatal hippocampus , 2004, The Journal of cell biology.

[45]  J. Schwob,et al.  Multipotency of purified, transplanted globose basal cells in olfactory epithelium , 2004, The Journal of comparative neurology.

[46]  S. Youngentob,et al.  Globose basal cells are required for reconstitution of olfactory epithelium after methyl bromide lesion , 2003, The Journal of comparative neurology.

[47]  V. Gallo,et al.  Postnatal NG2 proteoglycan–expressing progenitor cells are intrinsically multipotent and generate functional neurons , 2003, The Journal of cell biology.

[48]  B. Trapp,et al.  The tetraspanin protein, CD9, is expressed by progenitor cells committed to oligodendrogenesis and is linked to β1 integrin, CD81, and Tspan‐2 , 2002, Glia.

[49]  R. Cancedda,et al.  Replicative aging and gene expression in long-term cultures of human bone marrow stromal cells. , 2002, Tissue engineering.

[50]  A. Parent,et al.  The rostral migratory stream in adult squirrel monkeys: contribution of new neurons to the olfactory tubercle and involvement of the antiapoptotic protein Bcl‐2 , 2002, The European journal of neuroscience.

[51]  J. Schwob,et al.  Neural regeneration and the peripheral olfactory system , 2002, The Anatomical record.

[52]  John Quackenbush,et al.  Genesis: cluster analysis of microarray data , 2002, Bioinform..

[53]  A. LaMantia,et al.  Mesenchymal/Epithelial Induction Mediates Olfactory Pathway Formation , 2000, Neuron.

[54]  M. Pittenger,et al.  Multilineage potential of adult human mesenchymal stem cells. , 1999, Science.

[55]  A. Holley,et al.  Stress induces neurogenesis in non-neuronal cell cultures of adult olfactory epithelium , 1999, Neuroscience.

[56]  M. Luskin,et al.  Adult olfactory epithelium contains multipotent progenitors that give rise to neurons and non‐neural cells , 1998, The Journal of comparative neurology.

[57]  A. Mackay-Sim,et al.  New techniques for biopsy and culture of human olfactory epithelial neurons. , 1998, Archives of otolaryngology--head & neck surgery.

[58]  S. Youngentob,et al.  Transplantation of multipotent progenitors from the adult olfactory epithelium , 1998, Neuroreport.

[59]  A I Caplan,et al.  In vitro chondrogenesis of bone marrow-derived mesenchymal progenitor cells. , 1998, Experimental cell research.

[60]  S. Bruder,et al.  Growth kinetics, self‐renewal, and the osteogenic potential of purified human mesenchymal stem cells during extensive subcultivation and following cryopreservation , 1997, Journal of cellular biochemistry.

[61]  A. Mackay-Sim,et al.  Neurogenesis in adult human , 1996, Neuroreport.

[62]  M. Chuah,et al.  Olfactory Schwann cells are derived from precursor cells in the olfactory epithelium , 1991, Journal of neuroscience research.

[63]  C. Tickle,et al.  Epithelia are interchangeable between facial primordia of chick embryos and morphogenesis is controlled by the mesenchyme. , 1989, Developmental biology.

[64]  P. L. Hinds,et al.  An autoradiographic study of the mouse olfactory epithelium: Evidence for long‐lived receptors , 1984, The Anatomical record.

[65]  P. Graziadei,et al.  Neurogenesis and neuron regeneration in the olfactory system of mammals. II. Degeneration and reconstitution of the olfactory sensory neurons after axotomy , 1979, Journal of neurocytology.

[66]  P. Graziadei,et al.  Neurogenesis and neuron regeneration in the olfactory system of mammals. I. Morphological aspects of differentiation and structural organization of the olfactory sensory neurons , 1979, Journal of neurocytology.

[67]  J. Hinds,et al.  Neurogenesis in the adult rat: electron microscopic analysis of light radioautographs. , 1977, Science.

[68]  A. Cuschieri,et al.  The development of the olfactory mucosa in the mouse: electron microscopy. , 1975, Journal of anatomy.

[69]  D. G. Moulton,et al.  DYNAMICS OF CELL POPULATIONS IN THE OLFACTORY EPITHELIUM , 1974, Annals of the New York Academy of Sciences.

[70]  J. Altman Autoradiographic and histological studies of postnatal neurogenesis. IV. Cell proliferation and migration in the anterior forebrain, with special reference to persisting neurogenesis in the olfactory bulb , 1969, The Journal of comparative neurology.