Short-term exposure of multipotent stromal cells to low oxygen increases their expression of CX3CR1 and CXCR4 and their engraftment in vivo.
The ability of stem/progenitor cells to migrate and engraft into host tissues is key to their potential use in gene and cell therapy. Among the cells of interest are the adherent cells from bone marrow, referred to as mesenchymal stem cells or multipotent stromal cells (MSC). Since the bone marrow environment is hypoxic, with oxygen tensions ranging from 1% to 7%, we decided to test whether hypoxia can upregulate chemokine receptors and enhance the ability of human MSCs to engraft in vivo. Short-term exposure of MSCs to 1% oxygen increased expression of the chemokine receptors CX3CR1and CXCR4, both as mRNA and as protein. After 1-day exposure to low oxygen, MSCs increased in vitro migration in response to the fractalkine and SDF-1alpha in a dose dependent manner. Blocking antibodies for the chemokine receptors significantly decreased the migration. Xenotypic grafting into early chick embryos demonstrated cells from hypoxic cultures engrafted more efficiently than cells from normoxic cultures and generated a variety of cell types in host tissues. The results suggest that short-term culture of MSCs under hypoxic conditions may provide a general method of enhancing their engraftment in vivo into a variety of tissues.
Hung
Shih-Chieh
SC
Center for Gene Therapy, Tulane University Health Science Center, New Orleans, Louisiana, United States of America. hungsc@vghtpe.gov.tw
Pochampally
Radhika R
RR
Hsu
Shu-Ching
SC
Sanchez
Cecelia
C
Chen
Sy-Chi
SC
Spees
Jeffrey
J
Prockop
Darwin J
DJ
D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D002454:Cell Differentiation; D002459:Cell Fusion; D049109:Cell Proliferation; D002642:Chick Embryo; D006801:Humans; D039902:Multipotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D010100:Oxygen / Q000008:administration & dosage*; D012333:RNA, Messenger / Q000235:genetics; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism*
D000073883:CX3C Chemokine Receptor 1; C095235:CX3CR1 protein, human; C527276:CXCR4 protein, human; D012333:RNA, Messenger; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; D010100:Oxygen