G-CSF-mobilized Bone Marrow Mesenchymal Stem Cells Replenish Neural Lineages in Alzheimer’s Disease Mice via CXCR4/SDF-1 Chemotaxis
- 876 Downloads
Recent studies reported granulocyte colony-stimulating factor (G-CSF) treatment can improve the cognitive function of Alzheimer’s disease (AD) mice, and the mobilized hematopoietic stem cells (HSCs) or bone marrow mesenchymal stem cells (BM-MSCs) are proposed to be involved in this recovery effect. However, the exact role of mobilized HSC/BM-MSC in G-CSF-based therapeutic effects is still unknown. Here, we report that C-X-C chemokine receptor type 4 (CXCR4)/stromal cell-derived factor 1 (SDF-1) chemotaxis was a key mediator in G-CSF-based therapeutic effects, which was involved in the recruitment of repair-competent cells. Furthermore, we found both mobilized HSCs and BM-MSCs were able to infiltrate into the brain, but only BM-MSCs replenished the neural lineage cells and contributed to neurogenesis in the brains of AD mice. Together, our data show that mobilized BM-MSCs are involved in the replenishment of neural lineages following G-CSF treatment via CXCR4/SDF-1 chemotaxis and further support the potential use of BM-MSCs for further autogenically therapeutic applications.
KeywordsG-CSF Bone marrow stem cells SDF-1 CXCR4 Neurogenesis Alzheimer’s disease
The authors are grateful to Ya-Chun Hsiao for the services regarding image acquisition and analysis from the FACS-like tissue cytometry in the Center of Clinical Medicine, NCKU Hospital, and Ming-Tai Yu and Yi-Ru Gu for the technical support. This study is partly supported by NCKU Academic Summit Program and the Ministry of Science and Technology grant (MOST-105-2321-B-006-002, MOST-104-2321-B-006-010, MOST-103-2321-B-006 -028, MOST-105-2628-B-006-016-MY3, and NSC-102-2320-B-006-040-MY3).
Cheng-Chun conceived and designed the study, collected and assembled the data, analyzed and interpreted the data, and wrote the manuscript. I-Fang provisioned the study material and analyzed and interpreted the data. Po-Min conceived and designed the study and collected and assembled the data. Liang-Chao conceived and designed the study and collected and assembled the data. Che-Kun James provisioned the study material and analyzed and interpreted the data. Kuen-Jer conceived and designed the study, collected and assembled the data, analyzed and interpreted the data, wrote the manuscript, and approved the final version of manuscript.
Compliance with Ethical Standards
Conflicts of Interest
The authors have no conflict of interest in this study.
- 5.Lee JK, Jin HK, Endo S, Schuchman EH, Carter JE, Bae JS (2010) Intracerebral transplantation of bone marrow-derived mesenchymal stem cells reduces amyloid-beta deposition and rescues memory deficits in Alzheimer’s disease mice by modulation of immune responses. Stem Cells 28:329–343PubMedGoogle Scholar
- 10.Montzka K, Lassonczyk N, Tschoke B, Neuss S, Fuhrmann T, Franzen R, Smeets R, Brook GA et al (2009) Neural differentiation potential of human bone marrow-derived mesenchymal stromal cells: misleading marker gene expression. BMC Neurosci 10Google Scholar
- 15.Koda M, Nishio Y, Kamada T, Someya Y, Okawa A, Mori C, Yoshinaga K, Okada S et al (2007) Granulocyte colony-stimulating factor (G-CSF) mobilizes bone marrow-derived cells into injured spinal cord and promotes functional recovery after compression-induced spinal cord injury in mice. Brain Res 1149:223–231CrossRefPubMedGoogle Scholar
- 18.Shin JW, Lee JK, Lee JE, Min WK, Schuchman EH, Jin HK, Bae JS (2011) Combined effects of hematopoietic progenitor cell mobilization from bone marrow by granulocyte colony stimulating factor and AMD3100 and chemotaxis into the brain using stromal cell-derived factor-1alpha in an Alzheimer’s disease mouse model. Stem Cells 29:1075–1089CrossRefPubMedGoogle Scholar
- 26.Imitola J, Raddassi K, Park KI, Mueller FJ, Nieto M, Teng YD, Frenkel D, Li J et al (2004) Directed migration of neural stem cells to sites of CNS injury by the stromal cell-derived factor 1alpha/CXC chemokine receptor 4 pathway. Proc Natl Acad Sci U S A 101:18117–18122CrossRefPubMedPubMedCentralGoogle Scholar
- 27.Aiuti A, Webb IJ, Bleul C, Springer T, Gutierrez-Ramos JC (1997) The chemokine SDF-1 is a chemoattractant for human CD34+ hematopoietic progenitor cells and provides a new mechanism to explain the mobilization of CD34+ progenitors to peripheral blood. J Exp Med 185:111–120CrossRefPubMedPubMedCentralGoogle Scholar
- 32.Stumm RK, Rummel J, Junker V, Culmsee C, Pfeiffer M, Krieglstein J, Hollt V, Schulz S (2002) A dual role for the SDF-1/CXCR4 chemokine receptor system in adult brain: isoform-selective regulation of SDF-1 expression modulates CXCR4-dependent neuronal plasticity and cerebral leukocyte recruitment after focal ischemia. J Neurosci 22:5865–5878PubMedGoogle Scholar
- 36.Kawada H, Takizawa S, Takanashi T, Morita Y, Fujita J, Fukuda K, Takagi S, Okano H et al (2006) Administration of hematopoietic cytokines in the subacute phase after cerebral infarction is effective for functional recovery facilitating proliferation of intrinsic neural stem/progenitor cells and transition of bone marrow-derived neuronal cells. Circulation 113:701–710CrossRefPubMedGoogle Scholar
- 40.CC W, Lien CC, Hou WH, Chiang PM, Tsai KJ (2016) Gain of BDNF function in engrafted neural stem cells promotes the therapeutic potential for Alzheimer’s disease. Sci Rep 6:27358Google Scholar
- 46.Oglodek EA, Szota AM, Just MJ, Mos DM, Araszkiewicz A (2015) The MCP-1, CCL-5 and SDF-1 chemokines as pro-inflammatory markers in generalized anxiety disorder and personality disorders. Pharmacol Rep 67:85–89Google Scholar
- 48.Kitaori T, Ito H, Schwarz EM, Tsutsumi R, Yoshitomi H, Oishi S, Nakano M, Fujii N et al (2009) Stromal cell-derived factor 1/CXCR4 signaling is critical for the recruitment of mesenchymal stem cells to the fracture site during skeletal repair in a mouse model. Arthritis Rheum 60:813–823CrossRefPubMedGoogle Scholar
- 59.Spees JL, Olson SD, Ylostalo J, Lynch PJ, Smith J, Perry A, Peister A, Wang MY et al (2003) Differentiation, cell fusion, and nuclear fusion during ex vivo repair of epithelium by human adult stem cells from bone marrow stroma. Proc Natl Acad Sci U S A 100:2397–2402CrossRefPubMedPubMedCentralGoogle Scholar