Short Pulse of a Small Peptide Agonist of Stromal Cell-Derived Factor - 1 (SDF-1) Enhances the Engraftment of Expanded Human Cord Blood Hematopoietic Progenitor Cells in NOD/SCID Mice

• Published in: Blood Vol. 104; no. 11; p. 404
• Main Authors: Har Li, Karen Kwai, Chuen, Carmen K.Y., Lee, Shuk Man, Wong, Donald, Merzouk, Ahmed, Salari, Hassan, Yuen, Patrick M.P., Li, Chi Kong, Fok, Tai Fai, Gu, Goldie J.S., Tsang, Kam Sze, Chik, Ki Wai, Law, Ping
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 16-11-2004
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V104.11.404.404

SDF-1 is the ligand to the chemokine receptor CXCR-4. A small synthetic peptide agonist of SDF-1 (CTCE-0214) has been shown to expand human cord blood hematopoietic stem and progenitor cells. In this study, we investigated whether a brief exposure of expanded cord blood hematopoietic cells to CTCE-0214 can improve engraftment of the cells into NOD/SCID mice. Published in vivo studies demonstrated that the administration of CTCE-0214 to transplanted NOD/SCID mice mobilized human colony forming cells (CFC) and enhanced human thrombopoiesis (Exp Hematol 32, 300, 2004). Our earlier study showed that CTCE-0214 added to single factors of thrombopoietin (TPO), stem cell factor (SCF), or Flt-3 ligand (F3L) synergistically increased the survival of enriched cord blood CD34+ cells (Blood 102, 960a, 2003). In this study, we further investigated the effects of CTCE-0214 on the ex vivo expansion of CD34+ cells to multi-lineage progenitors and the homing and engraftment capacity of expanded human progenitor cells after a short in vitro exposure to the peptide prior to infusion into NOD/SCID mice. Enriched CD34+ cells (MACS) derived from cord blood were cultured for 8 days in serum-free medium QBSF-60 containing TPO (50 ng/ml), SCF (50 ng/nl) and F3L (80 ng/ml) (TSF), with or without CTCE-0214 (0.01 ng/ml) (TSF+CTCE-0214) added at day 4. Progenitor cells expanded for 8 days in the absence of CTCE-0214 were pulsed with the peptide (100 ng/ml) for 4 hours (TSFpCTCE-0214). Results are summarized in Table. CTCE-0214 significantly (N=30, p≤0.05, paired t-test) increased the fold expansion of total nucleated cells (TNC), CD34+ cells, CD34+CD38- cells, CFU-GM, CFU-E, and CFU-MK (total CFC). Expanded progenitor cells (with and without CTCE-0214) were then infused into irradiated NOD/SCID mice. After 6 weeks, enhanced engraftments of human CD45+ cells (p≤0.05, N=21) were demonstrated in the bone marrow (BM) of mice that received cells cultured in TSF+CTCE-0214. Interestingly, a short pulse of cells expanded in TSF to CTCE-0214 for 4 hours also significantly increased the NOD/SCID engraftment (N=18), although no major changes to the in vitro read-out parameters were observed. The mechanism could be associated with the increased homing capacity of progenitor cells after pulsing with CTCE-0214. In conclusion, our results showed that CTCE-0214 enhances the proliferation of early progenitor cells in culture and exposure to the peptide can enhance the engraftment potential of expanded cells in NOD/SCID mice. The SDF-1 peptide agonist could be developed for application to hematopoietic stem cell transplantation and ex vivo expansion.
NOD/SCID Engraftment of Expanded Cord Blood Stem Cells
TSFTSF+CTCE-0214TSFpCTCE-0214TNC*84.6±10.4123.5±15.388.5±11.2CD34+*8.5±1.314.1±2.19.6±1.6CD34+CD38−*24.6±4.848.7±8.627.5±5.3Total CFC*46.9±6.587.9±10.750.6±6.4NOD/SCID**2.8±0.96.7±2.58.3±4.0*Fold expansion (mean±SE); **% human CD45+ cells in BM of mice