Multiple Human Progenitor Lineages Mediate the Endogenous Regeneration of Beta Cells Via Pro-Angiogenic and Putative Neogenic Function.
Notice bibliographique
Résumé
Abstract Abstract 2426 Poster Board II-403 In the context of regenerative therapies for diabetes, the contributions of transplanted stem cells are not limited to the direct replacement of damaged beta cells. We previously established that transplanted murine bone marrow (BM) stem cells stimulate endogenous beta cell proliferation and insulin production resulting in improved glycemic control. To enrich for analogous human progenitor subtypes that promote beta cell regeneration, we FACS-purified human BM and umbilical cord blood (UCB) cells based on aldehyde dehydrogenase (ALDH) activity, a conserved enzymatic function in multiple progenitor lineages. Compared to ALDHlo cells, ALDHhi cells from both human sources were enriched for progenitor phenotype, possessed multipotent hematopoietic colony forming cell function in vitro, and reconstitute hematopoiesis in NOD/SCID recipients. Human BM-derived ALDHhi cells also contained multipotent mesenchymal colony forming cells (MCFC) (1 in 1.4×103, n=5), whereas ALDHlo cells established infrequent but expandable MCFC clones restricted to the adipose lineage. In contrast, both human UCB-derived ALDH-purified populations were devoid of MCFC capacity but the ALDHhi population was enriched for endothelial colony forming cells (ECFC) (1 in 5.8×104, n=4). To address beta cell regeneration in vivo, hyperglycemic (multiple low dose STZ-treated) NOD/SCID mice were tail vein injected with purified human ALDHlo or ALDHhi cells after sublethal (300cGy) preparative irradiation and blood glucose was monitored for >30 days. Compared to PBS injected controls (n=12), transplantation of BM-derived ALDHlo (n=8) or ALDHhi (n=10) cells induced a 2-fold decrease in systemic blood glucose concentrations within 7 days post transplantation, and significantly (p<0.01) reduced glycemia was maintained for >30 days. In contrast, the UCB-derived ALDHhi population induced only a transient reduction of systemic blood glucose 7-18 days post-transplant, with the return of hyperglycemia and hypoinsulinemia by 30 days post-transplantation. Taken together, these data implicate the human BM mesenchmal lineage in hyperglycemia reduction. Although UCB-derived ALDHhi cells did not augment the total islet number or beta cell mass at 30 days post-transplantation, ALDHhi cell transplanted mouse pancreata contained significantly larger (p<0.05) insulin+ islets with increased vWF+ vessel density (p<0.05) compared to PBS controls, indicating that transiently reduced blood glucose may be due to beneficial pro-angiogenic effects of these cells on islet vascularization. To further investigate the direct role of transplanted MSC subtypes in glycemic recovery, ex vivo expanded ALDHlo-MSC or ALDHhi-MSC from 6 paired human BM samples were transplanted into hyperglycemic recipients and murine pancreata were analyzed for the endogenous regeneration of insulin+ islets. For 2 independent BM samples, transplantation of both ALDHlo-MSC or ALDHhi-MSC did not reduce established hyperglycemia, increase serum insulin, or show regeneration of insulin+ islets compared to PBS controls. For the remaining 4 BM samples, mice injected with cultured human BM ALDHlo-MSC (n=16) or BM ALDHhi-MSC (n=19) demonstrated permanently reduced systemic hyperglycemia and significantly increased serum insulin at 30 days post-transplantation (p<0.05). In contrast to UCB-transplanted mice, transplantation of cultured BM ALDH purified-MSC induced a significant increase (p<0.05) in islet number and beta cell mass, without an increase in islet size, suggesting that BM-derived MSC may initiate islet neogenesis. Thus, independent human BM samples showed variable capacity to regenerate islets, suggesting that cell type independent or extrinsic factors may also impact the regenerative capacity of human MSC. Finally, prolonged expansion of BM-derived MSC diminished the ability of transplanted cells to improve hyperglycemia. In summary, ALDHhi mixed progenitor cells from human UCB contain pro-angiogenic progenitor subtypes that augment islet size and vascularization after transplantation, whereas expanded human BM-derived MSC increase regenerating islet number and total beta cell mass via a putative neogenic mechanism. Further characterization of the divergent pro-angiogenic and neogenic mechanisms by which specific cell types promote beta cell regeneration may provide new approaches for cellular therapy in diabetes. Disclosures: No relevant conflicts of interest to declare.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,006 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».