Regeneration potential and survival of transplanted undifferentiated adipose tissue-derived stem cells in peripheral nerve conduits.

Adipose tissue-derived stem cells (ADSCs) have shown potential for the treatment of nerve injuries. Most previous efforts have aimed at stimulating regeneration by using neural-differentiation protocols, but the potential of undifferentiated ADSCs to enhance axonal growth as well as their ability to transdifferentiate in situ have been poorly investigated. In this study, using a rat sciatic nerve model we show that ADSCs, transplanted in an artificial nerve conduit, stimulate axonal outgrowth from the proximal nerve stump and evoke greater Schwann cell (SC) proliferation/intrusion in the distal stump. To track the fate of the transplanted cells, we used green fluorescent protein (GFP)-labelling and polymerase chain reaction (PCR) for the detection of the sex determining region Y (SRY) gene in the donor male cells. Both methods indicated a lack of significant quantities of viable cells 14 days after transplantation. These results suggest that any regenerative effect of transplanted ADSCs is more likely to be mediated by an initial boost of released growth factors and/or by an indirect effect on endogenous SCs activity. Future studies need to address long-term cell survival in tissue-engineered nerve conduits to improve the neuroregenerative potential of ADSCs.

[1]  H. Hampel,et al.  IFATS Collection: The Conditioned Media of Adipose Stromal Cells Protect Against Hypoxia‐Ischemia‐Induced Brain Damage in Neonatal Rats , 2009, Stem cells.

[2]  D. Prockop,et al.  Engraftment and migration of human bone marrow stromal cells implanted in the brains of albino rats--similarities to astrocyte grafts. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[3]  C. Dani,et al.  Nucleofection Is a Valuable Transfection Method for Transient and Stable Transgene Expression in Adipose Tissue‐Derived Stem Cells , 2007, Stem cells.

[4]  Mikael Wiberg,et al.  Effect of Allogeneic Schwann Cell Transplantation on Peripheral Nerve Regeneration , 2002, Experimental Neurology.

[5]  G. Evans,et al.  Long-term maintenance of neuronally differentiated human adipose tissue-derived stem cells. , 2007, Tissue engineering.

[6]  S. Hsu,et al.  Transplantation of bone marrow stromal cells for peripheral nerve repair , 2007, Experimental Neurology.

[7]  S. Hall.  The response to injury in the peripheral nervous system. , 2005, The Journal of bone and joint surgery. British volume.

[8]  P. Wood,et al.  Labeled Schwann cell transplantation: Cell loss, host Schwann cell replacement, and strategies to enhance survival , 2006, Glia.

[9]  Mikael Wiberg,et al.  Adipose-derived stem cells differentiate into a Schwann cell phenotype and promote neurite outgrowth in vitro , 2007, Experimental Neurology.

[10]  W. Wilkison,et al.  Extracellular matrix mineralization and osteoblast gene expression by human adipose tissue-derived stromal cells. , 2001, Tissue engineering.

[11]  Cheng He,et al.  The effect of bone marrow stromal cells on neuronal differentiation of mesencephalic neural stem cells in Sprague–Dawley rats , 2003, Brain Research.

[12]  K. Conant,et al.  Transplanted neural stem cells promote axonal regeneration through chronically denervated peripheral nerves , 2004, Experimental Neurology.

[13]  J. Jenkins,et al.  NGF gene expression and secretion in white adipose tissue: regulation in 3T3-L1 adipocytes by hormones and inflammatory cytokines. , 2004, American journal of physiology. Endocrinology and metabolism.

[14]  Yao‐Hua Song,et al.  The cardioprotective effect of mesenchymal stem cells is mediated by IGF-I and VEGF. , 2007, Biochemical and biophysical research communications.

[15]  W. Wilkison,et al.  Neurogenic differentiation of murine and human adipose-derived stromal cells. , 2002, Biochemical and biophysical research communications.

[16]  Ryuichi Morishita,et al.  Adipose tissue-derived stromal cells as a novel option for regenerative cell therapy. , 2006, Journal of atherosclerosis and thrombosis.

[17]  S. Shimizu,et al.  Peripheral nerve regeneration by the in vitro differentiated-human bone marrow stromal cells with Schwann cell property. , 2007, Biochemical and biophysical research communications.

[18]  G. Terenghi,et al.  VEGF enhances intraneural angiogenesis and improves nerve regeneration after axotomy , 2000, Journal of anatomy.

[19]  G. Terenghi,et al.  Peripheral nerve regeneration and neurotrophic factors , 1999, Journal of anatomy.

[20]  G. Pierer,et al.  Fibrin matrix for suspension of regenerative cells in an artificial nerve conduit. , 2008, Journal of plastic, reconstructive & aesthetic surgery : JPRAS.

[21]  M. Hedrick,et al.  Multipotential differentiation of adipose tissue-derived stem cells. , 2005, The Keio journal of medicine.

[22]  D. Pleasure,et al.  Peripheral nerve regeneration is delayed in neuropilin 2–deficient mice , 2008, Journal of neuroscience research.

[23]  Jeff Biernaskie,et al.  Skin-Derived Precursors Generate Myelinating Schwann Cells for the Injured and Dysmyelinated Nervous System , 2006, The Journal of Neuroscience.

[24]  C. Idé.  Peripheral nerve regeneration , 1996, Neuroscience Research.

[25]  M. Fishbein,et al.  Mesenchymal Stem Cell Injection Induces Cardiac Nerve Sprouting and Increased Tenascin Expression in a Swine Model of Myocardial Infarction , 2003, Journal of cardiovascular electrophysiology.

[26]  A. Katz,et al.  Mesenchymal stem cells from rat visceral fat exhibit multipotential differentiation in vitro. , 2003, The anatomical record. Part A, Discoveries in molecular, cellular, and evolutionary biology.

[27]  Min Zhu,et al.  Comparison of Multi-Lineage Cells from Human Adipose Tissue and Bone Marrow , 2003, Cells Tissues Organs.

[28]  Shiaw-Min Hwang,et al.  Combination of G-CSF Administration and Human Amniotic Fluid Mesenchymal Stem Cell Transplantation Promotes Peripheral Nerve Regeneration , 2009, Neurochemical Research.

[29]  S. Kang,et al.  Interactions between human adipose stromal cells and mouse neural stem cells in vitro. , 2003, Brain research. Developmental brain research.

[30]  M. Wiberg,et al.  Rat bone marrow mesenchymal stem cells express glial markers and stimulate nerve regeneration , 2004, Neuroscience Letters.

[31]  G. Keilhoff,et al.  Transdifferentiation of mesenchymal stem cells into Schwann cell-like myelinating cells. , 2006, European journal of cell biology.

[32]  G. Lundborg,et al.  Vascular Endothelial Growth Factor Has Neurotrophic Activity and Stimulates Axonal Outgrowth, Enhancing Cell Survival and Schwann Cell Proliferation in the Peripheral Nervous System , 1999, The Journal of Neuroscience.

[33]  Keith L. March,et al.  Secretion of Angiogenic and Antiapoptotic Factors by Human Adipose Stromal Cells , 2004, Circulation.

[34]  B. Johnstone,et al.  Adipose stromal cells-conditional medium protected glutamate-induced CGNs neuronal death by BDNF , 2009, Neuroscience Letters.

[35]  Min Zhu,et al.  Human adipose tissue is a source of multipotent stem cells. , 2002, Molecular biology of the cell.

[36]  M. Fishbein,et al.  IFATS Collection: Human Adipose Tissue‐Derived Stem Cells Induce Angiogenesis and Nerve Sprouting Following Myocardial Infarction, in Conjunction with Potent Preservation of Cardiac Function , 2009, Stem cells.

[37]  W. Thompson,et al.  Schwann cell processes guide regeneration of peripheral axons , 1995, Neuron.

[38]  Radovan Borojevic,et al.  Bone marrow stromal cells and resorbable collagen guidance tubes enhance sciatic nerve regeneration in mice , 2006, Experimental Neurology.

[39]  M. Wiberg,et al.  Phenotypic and functional characteristics of mesenchymal stem cells differentiated along a Schwann cell lineage , 2006, Glia.

[40]  L Sedel,et al.  A biodegradable fibrin scaffold for mesenchymal stem cell transplantation. , 2003, Biomaterials.

[41]  Charles Tator,et al.  Analysis of Green Fluorescent Protein Expression in Transgenic Rats for Tracking Transplanted Neural Stem/Progenitor Cells , 2005, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[42]  Kenneth Cornetta,et al.  Suppression of Hepatocyte Growth Factor Production Impairs the Ability of Adipose‐Derived Stem Cells to Promote Ischemic Tissue Revascularization , 2007, Stem cells.

[43]  Farshid Guilak,et al.  Chondrogenic potential of adipose tissue-derived stromal cells in vitro and in vivo. , 2002, Biochemical and biophysical research communications.

[44]  Masahiko Takano,et al.  Sciatic nerve regeneration in rats induced by transplantation of in vitro differentiated bone‐marrow stromal cells , 2001, The European journal of neuroscience.

[45]  A. Farini,et al.  Skin‐derived stem cells transplanted into resorbable guides provide functional nerve regeneration after sciatic nerve resection , 2007, Glia.