Aldehyde dehydrogenase 1 activity in the developing human pancreas modulates retinoic acid signalling in mediating islet differentiation and survival

Li, Jinming; Feng, Zhi C.; Yeung, Frances S.-H.; Wong, Melanie R.-M.; Oakie, Amanda; Fellows, George F; Goodyer, Cynthia G.; Hess, David A.; Wang, Rennian

doi:10.1007/s00125-013-3147-y

Cited by 34 publications

(25 citation statements)

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“…Previous research from our group and others have shown that high ALDH‐activity is a conserved function of multiple stem and progenitor cell lineages including endothelial precursors , mesenchymal stem cells , neural progenitors , muscle precursors , and pancreatic endocrine precursors among others (reviewed in ref. ).…”

Section: Discussionmentioning

confidence: 99%

Expanded Hematopoietic Progenitor Cells Reselected for High Aldehyde Dehydrogenase Activity Demonstrate Islet Regenerative Functions

et al. 2016

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Human umbilical cord blood (UCB) hematopoietic progenitor cells (HPC) purified for high aldehyde dehydrogenase activity (ALDH hi ) stimulate islet regeneration after transplantation into mice with streptozotocin-induced b cell deletion. However, ALDH hi cells represent a rare progenitor subset and widespread use of UCB ALDH hi cells to stimulate islet regeneration will require progenitor cell expansion without loss of islet regenerative functions. Here we demonstrate that prospectively purified UCB ALDH hi cells expand efficiently under serum-free, xeno-free conditions with minimal growth factor supplementation. Consistent with the concept that ALDHactivity is decreased as progenitor cells differentiate, kinetic analyses over 9 days revealed the frequency of ALDH hi cells diminished as culture time progressed such that total ALDH hi cell number was maximal (increased 3-fold) at day 6. Subsequently, day 6 expanded cells (bulk cells) were sorted after culture to reselect differentiated progeny with low ALDH-activity (ALDH lo subset) from less differentiated progeny with high ALDH-activity (ALDH hi subset). The ALDH hi subset retained primitive cell surface marker coexpression (32.0% 6 7.0% CD34 1 /CD38 2 cells, 37.0% 6 6.9% CD34 1 /CD133 1 cells), and demonstrated increased hematopoietic colony forming cell function compared with the ALDH lo subset. Notably, bulk cells or ALDH lo cells did not possess the functional capacity to lower hyperglycemia after transplantation into streptozotocin-treated NOD/SCID mice. However, transplantation of the repurified ALDH hi subset significantly reduced hyperglycemia, improved glucose tolerance, and increased isletassociated cell proliferation and capillary formation. Thus, expansion and delivery of reselected UCB cells that retain high ALDH-activity after short-term culture represents an improved strategy for the development of cellular therapies to enhance islet regeneration in situ. STEM CELLS 2016;34:873-887 SIGNIFICANCE STATEMENTAlthough fresh umbilical cord blood ALDHhi cells represent a promising population for the stimulation of islet regeneration, the low number of ALDHhi cells in UCB limits widespread application in diabetic patients. Clinical use of UCB ALDHhi cells to treat diabetes will require expansion without compromising previously reported islet regenerative functions. In order to generate more ALDHhi cells for regenerative applications, we developed a clinically applicable culture protocol that resulted in a significant increase in ALDHhi cells in 6 days. High ALDHexpression was diminished as culture time progressed. Therefore, we re-selected expanded progeny using ALDH-activity after culture, and compared the islet regenerative function of more differentiated (ALDHlo) versus less differentiated (ALDHhi) subsets. Compared to expanded progeny with low ALDH activity, the ALDHhi cell subset more highly expressed primitive cell surface markers, and demonstrated a pro-angiogenic transcription signature and enhanced hematopoietic colony formation in vi...

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Section: Discussionmentioning

confidence: 99%

Expanded Hematopoietic Progenitor Cells Reselected for High Aldehyde Dehydrogenase Activity Demonstrate Islet Regenerative Functions

et al. 2016

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“…As a major active metabolite of vitamin A (retinol), all-trans retinoic acid (RA) functions as a natural ligand for retinoic acid receptor and retinoid X receptor (RXR), nuclear hormone receptors that regulate the transcription of different kinds of genes controlling cell differentiation, embryonic development, and physiologic homeostasis (5,6). RA is an effective chemotherapeutic agent for acute promyelocytic leukemia for its transcriptional activation of RXRs (7)(8)(9).…”

Section: Nonalcoholic Fatty Liver Disease (Nafld)mentioning

confidence: 99%

Association of serum retinoic acid with hepatic steatosis and liver injury in nonalcoholic fatty liver disease

Liu

Chen

Wang

et al. 2015

The American Journal of Clinical Nutrition

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Background: Retinoic acid (RA), an active metabolite of vitamin A (retinol), has been implicated in the regulation of lipid metabolism and hepatic steatosis in animal models. However, the relation between RA and liver histology in patients with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is unknown. Objective: This study aimed at examining the association of RA with NAFLD and NASH in Chinese subjects. Design: Serum RA concentration was determined by ELISA in 41 control subjects, 45 patients with NAFLD, and 38 patients with NASH. The associations of RA with adiposity, serum glucose, lipid profiles, and markers of liver damage were studied. Moreover, both mRNA and protein levels of retinoic X receptor a (RXRa) in the liver were analyzed in subjects with different degrees of hepatic steatosis. Results: Serum RA concentrations in patients with NAFLD (1.42 6 0.47 ng/mL) and NASH (1.14 6 0.26 ng/mL) were significantly lower than those in control subjects (2.70 6 0.52 ng/mL) (P , 0.01). Furthermore, serum RA concentrations were significantly different between subjects with normal glucose tolerance and those with type 2 diabetes in control [2.87 6 0.52 (n = 28) vs. 2.32 6 0.44 ng/mL (n = 13)], NAFLD [1.61 6 0.37 (n = 29) vs. 1.28 6 0.41 ng/mL (n = 16)], and NASH [1.35 6 0.34 (n = 24) vs. 1.07 6 0.29 ng/mL (n = 14)] groups. In human liver tissue, RXRa mRNA expression was inversely correlated with the exacerbation of hepatic steatosis. Both serum RA concentrations and RXRa mRNA levels were inversely correlated with intrahepatic triglyceride content (r = -0.700, P , 0.001, and r = -0.611, P = 0.002, respectively). Compared with grade 0 severity, the concentration of RXRa protein was lower in more severe grades in patients with NAFLD. Conclusion: These results show that circulating RA concentrations were lower in subjects with NAFLD and were associated with hepatic lipid metabolism and insulin resistance. This trial was registered at clinicaltrials.gov as NCT01940263.Am J Clin Nutr 2015;102:130-7.

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“…23 Recently, the importance of ALDH1A1 for differentiating endocrine precursor cells in pancreas was reported. 24,25 In our cohort, ALDH1A1 expression was relatively homogeneous within individual insulinomas (instead of a 'stem cell' pattern), indicating an early clonal selection towards ALDH1A1-overexpressing cells in malignant insulinomas.…”

Section: Discussionmentioning

confidence: 75%

Novel prognostic markers revealed by a proteomic approach separating benign from malignant insulinomas

et al. 2015

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The prognosis of pancreatic neuroendocrine tumors is related to size, histology and proliferation rate. However, this stratification needs to be refined further. We conducted a proteome study on insulinomas, a well-defined pancreatic neuroendocrine tumor entity, in order to identify proteins that can be used as biomarkers for malignancy. Based on a long follow-up, insulinomas were divided into those with metastases (malignant) and those without (benign). Microdissected cells from six benign and six malignant insulinomas were subjected to a procedure combining fluorescence dye saturation labeling with high-resolution two-dimensional gel electrophoresis. Differentially expressed proteins were identified using nano liquid chromatography-electrospray ionization/multi-stage mass spectrometry and validated by immunohistochemistry on tissue microarrays containing 62 insulinomas. Sixteen differentially regulated proteins were identified among 3000 protein spots. Immunohistochemical validation revealed that aldehyde dehydrogenase 1A1 and voltage-dependent anion-selective channel protein 1 showed significantly stronger expression in malignant insulinomas than in benign insulinomas, whereas tumor protein D52 (TPD52) binding protein was expressed less strongly in malignant insulinomas than in benign insulinomas. Using multivariate analysis, low TPD52 expression was identified as a strong independent prognostic factor for both recurrence-free and overall disease-related survival.

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Aldehyde dehydrogenase 1 activity in the developing human pancreas modulates retinoic acid signalling in mediating islet differentiation and survival

Cited by 34 publications

References 50 publications

Expanded Hematopoietic Progenitor Cells Reselected for High Aldehyde Dehydrogenase Activity Demonstrate Islet Regenerative Functions

Expanded Hematopoietic Progenitor Cells Reselected for High Aldehyde Dehydrogenase Activity Demonstrate Islet Regenerative Functions

Association of serum retinoic acid with hepatic steatosis and liver injury in nonalcoholic fatty liver disease

Novel prognostic markers revealed by a proteomic approach separating benign from malignant insulinomas

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