Augmented Revascularization and Recovery From Acute Limb Ischemia After Transplantation of Human Umbilical Cord Blood Progenitor Cells with High Aldehyde Dehydrogenase Activity

Autor: David A. Hess, Debra L. Robson, Heather C. Broughton, Gillian I. Bell, David M. Putman
Rok vydání: 2009
Předmět:
Zdroj: Blood. 114:3042-3042
ISSN: 1528-0020
0006-4971
DOI: 10.1182/blood.v114.22.3042.3042
Popis: Abstract 3042 Poster Board II-1018 Clinical application of regenerative cell-based therapies for the treatment of ischemic vascular disease has proven challenging to implement due the involvement of multiple human cell types that co-ordinate angiogenesis. Previously, transplanted human progenitor cells from hematopoietic, endothelial, and mesenchymal lineages have all been implicated in the recovery and de novo production of perfused blood vessels in vivo. Using high aldehyde dehydrogenase (ALDHhi) activity, a conserved function of these pro-angiogenic hematopoietic and non-hematopoietic progenitor cell lineages, we have recently shown that transplanted human bone marrow (BM) ALDHhi cells transiently recruit to areas of hypoxia and augment revascularization and recovery of perfusion in ischemic limbs via the stimulation of endogenous vascular regeneration. However, clinical use of autologous BM-derived cells in patients with critical limb ischemia may be limited by the availability or dysfunction of transplanted pro-angiogenic cells due to vascular disease-related pathologies. The non-invasive collection and early ontogeny of human umbilical cord blood (UCB) progenitor cells provides a promising alternative source of pro-angiogenic progenitor cells with vascular regenerative functions. Human UCB mononuclear cells (MNC) were purified using high-speed fluorescence-activated cell sorting to accrue clinically applicable cell populations with low side scatter and high (ALDHhi, 0.4±0.1% of total MNC) versus low (ALDHlo, 41.2±3.6% of total MNC) ALDH activity (n=10). Compared to UCB-derived ALDHlo cells, which were devoid of hematopoietic and non-hematopoietic progenitor function in vitro, ALDHhi cells were enriched for hematopoietic colony forming cells (1 HCFC in 3.6 cells, n=4) and endothelial colony forming cells (1 ECFC in 5.8×104 cells, n=4) enumerated after 14 days in culture. In contrast to human BM-derived ALDH-purified cells which were enriched for mesenchymal colony forming cells, analogous ALDHlo and ALDHhi cells from UCB did not establish mesenchymal-stromal colonies in vitro suggesting a comparative deficiency in mesenchymal stem cell frequency after UCB venipuncture. We investigated the vascular regenerative capacity of these human UCB-derived ALDHlo and ALDHhi cells by tail-vein transplantation into sublethally irradiated (275cGy) immune-deficient, β-glucuronidase (GUSB) deficient, NOD/SCID/MPSVII mice with acute limb ischemia induced by unilateral femoral artery ligation and transection. Using weekly laser Doppler perfusion imaging to track the kinetics of blood flow recovery indicated by the perfusion ratio (PR) in the ischemic versus non-ischemic limb, mice transplanted with 2×105-4×105 purified ALDHhi cells showed significantly improved recovery of limb perfusion by day 21 post-transplantation (PR=0.70±0.06, n=6) compared to mice injected with phosphate-buffered saline (PR=0.35±0.06, n=5, P Disclosures No relevant conflicts of interest to declare.
Databáze: OpenAIRE
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