19: Pharmacologic Inhibition of Aldehyde Dehydrogenase (ALDH) Causes The Expansion of Hematopoietic Stem Cells (HSCs) with Enhanced Engraftment Capacity
Year: 2008
Type: article
Abstract: Delayed engraftment and graft failure are persistent obstacles which limit the application of umbilical cord blood (CB) transplantation in adults. We recently demonstrated that inhibition of ALDH with diethylaminobenzaldehyde (DEAB) induced the expansion of human HSCs capable of repopulating NOD/SCID mice (PNAS 2006 103:11707). In this study, we utilized syngeneic CD45.1/CD45.2 mice to determine whether inhibition of ALDH could accelerate the engraftment of transplanted HSCs in vivo. Culture of murine c-kit+sca-1+lin-CD34- (34-KSL) cells with 100 μM DEAB coupled with thrombopoietin, SCF and Flt-3 ligand (TSF) for 7 days resulted in a 22.6-fold expansion of total cells, compared with 360.0-fold expansion with TSF alone (p = 0.001). However, DEAB-culture maintained a significantly higher percentage of lin- (mean 97.1%) and KSL cells (mean 14.1%) at day 7 as compared to TSF alone (42.6% and 4.7%, respectively; p < 0.001 and p = 0.03), indicating that inhibition of ALDH preferentially maintained more primitive progenitors in culture than TSF alone. We then transplanted FACS-sorted donor CD45.1+ BM 34-KSL cells or their progeny following culture with TSF alone or TSF + DEAB at limiting doses into lethally irradiated CD45.2+ congenic recipients. At 4 weeks post-transplantat, DEAB-cultured progeny showed significantly accelerated engraftment in recipient mice, as compared to day 0 34-KSL cells or their progeny following culture with TSF alone. Using Poisson statistical analysis, the repopulating cell frequency was found to be 1 in 48.4 for the DEAB-cultured progeny (95% confidence interval: 27.3 – 86.0) as compared to 1 in 99.6; CI: 50.4 – 197.0) within the TSF-cultured progeny. Unmanipulated BM 34-KSL cells had not yet shown significant levels of hematopoietic engraftment at week 4 (1 in 1319.4; CI 187.2 – 9298.8). DEAB-cultured progeny also demonstrated significantly higher B220+ and Thy 1.2+ lymphoid contribution, as compared to day 0 BM 34-KSL cells (p < 0.001 and p < 0.001), and significantly higher level of Mac-1+/Gr-1+ myeloid reconstitution (p < 0.001), compared with the progeny of TSF alone. These data demonstrate that pharmacologic inhibition of ALDH facilitates the differential expansion of hematopoietic progenitors with enhanced early engraftment capacity. This strategy can be particularly useful to expand human CB grafts to overcome the delays in engraftment which currently limit this otherwise attractive source of HSCs for adult transplantation.
Institution: Duke University
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,650
OpenAlex ID: W2108866734