Augmented Revascularization and Recovery From Acute Limb Ischemia After Transplantation of Human Umbilical Cord Blood Progenitor Cells with High Aldehyde Dehydrogenase Activity.
Bibliographic record
Abstract
Abstract 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<0.01), 10×106 ALDHlo cells (PR=0.45±0.07, n=7, P<0.01), or 20×106 unpurified UCB MNC (PR=0.40±0.06, n=7, P<0.01). Furthermore, transplantation of ALDHhi progenitor cells augmented revascularization in the ischemic limb compared to all other treatments at day 28 post-transplantation (P<0.01), quantified by immunohistochemical detection and enumeration of von Willebrand factor+ blood vessels in frozen sections from the ischemic adductor muscle. Only mice transplanted with ALDHhi cells showed retention of human hematopoietic (CD45+/HLA-A,B,C+) cells in the ischemic adductor muscle for 28 days (3.0±2.1%, n=6) quantified by flow cytometry. Ischemic muscle sections from NOD/SCID/MPSVII mice transplanted with human UCB ALDHhi cells confirmed human cell retention and engraftment adjacent to damaged vasculature and ischemic muscle fibres at day 28 post-transplantation, measured by colorimetric detection of ubiquitous GUSB activity in transplanted human cells. Human UCB-derived ALDHhi cells, which were devoid of mesenchymal-stromal cells but enriched for potentially pro-angiogenic endothelial and hematopoietic progenitor lineages, showed persistent retention in areas of hypoxia and augmented the endogenous revascularization and recovery of perfusion in ischemic limbs. Thus, ALDHhi mixed progenitor cells may prove to be a useful allogeneic alternative to human BM in the clinical treatment of patients with severe peripheral vascular disease. Disclosures No relevant conflicts of interest to declare.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".