scholarly journals The functional role of chondrogenic stem/progenitor cells: novel evidence for immunomodulatory properties and regenerative potential after cartilage injury

2018 ◽  
Vol 36 ◽  
pp. 110-127 ◽  
Author(s):  
J Riegger ◽  
◽  
HG Palm ◽  
RE Brenner
Keyword(s):  
Progenitor Cells ◽  
Functional Role ◽  
Cartilage Injury ◽  
Immunomodulatory Properties

Identification of antisense lncRNAs targeting GSK3β as a regulator in major depressive disorder

Epigenomics ◽  
2020 ◽  
Vol 12 (19) ◽  
pp. 1725-1738
Author(s):  
Zhifen Liu ◽  
Xinrong Li ◽  
Chen Chen ◽  
Ning Sun ◽  
Yanfang Wang ◽  
...  
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Progenitor Cells ◽  
Functional Role ◽  
Functional Study ◽  
Major Depressive ◽  
Before And After ◽  
Antisense Lncrnas ◽  
Novel Therapeutic

Aim: To identify lncRNAs targeting GSK3β in MDD. Materials & methods: The levels of GSK3β and its three targeting lncRNAs (gsk3β antisense AS1, AS2 and AS3) were detected in 52 patients with major depressive disorder (MDD) before and after 8 weeks of escitalopram treatment. The functional study was evaluated using the silence of lncR-gsk3βAS2/3. The correlation between lncRNA-gsk3β and 89 MDD patients was analyzed. Human neuron progenitor cells were used to investigate the functional role of lncRNA-gsk3β in MDD. Results: All three lncRNAs were downregulated in MDD patients but upregulated after treatment. Inhibition of gsk3βAS2/3 reduced GSK3β expression and its phosphorylation levels in the neuron progenitor cells. Conclusion: Our findings suggest that lncRNA-gsk3βAS3 regulates GSK3β activity in MDD and has potential as a novel therapeutic target.

scholarly journals Functional Role of CLIC1 Ion Channel in Glioblastoma-Derived Stem/Progenitor Cells

2013 ◽  
Vol 105 (21) ◽  
pp. 1644-1655 ◽  
Author(s):  
Matteo Setti ◽  
Nicoletta Savalli ◽  
Daniela Osti ◽  
Cristina Richichi ◽  
Marina Angelini ◽  
...  
Keyword(s):  
Ion Channel ◽  
Progenitor Cells ◽  
Functional Role

scholarly journals CHIR99021 Augmented the Function of Late Endothelial Progenitor Cells by Preventing Replicative Senescence

2021 ◽  
Vol 22 (9) ◽  
pp. 4796
Author(s):  
Vinoth Kumar Rethineswaran ◽  
Da Yeon Kim ◽  
Yeon-Ju Kim ◽  
WoongBi Jang ◽  
Seung Taek Ji ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Progenitor Cells ◽  
Endothelial Progenitor Cells ◽  
Blood Circulation ◽  
Functional Role ◽  
Replicative Senescence ◽  
Endothelial Progenitor ◽  
Vascular Structures ◽  
Gsk 3Β

Endothelial progenitor cells (EPCs) are specialized cells in circulating blood, well known for their ability to form new vascular structures. Aging and various ailments such as diabetes, atherosclerosis and cardiovascular disease make EPCs vulnerable to decreasing in number, which affects their migration, proliferation and angiogenesis. Myocardial ischemia is also linked to a reduced number of EPCs and their endothelial functional role, which hinders proper blood circulation to the myocardium. The current study shows that an aminopyrimidine derivative compound (CHIR99021) induces the inhibition of GSK-3β in cultured late EPCs. GSK-3β inhibition subsequently inhibits mTOR by blocking the phosphorylation of TSC2 and lysosomal localization of mTOR. Furthermore, suppression of GSK-3β activity considerably increased lysosomal activation and autophagy. The activation of lysosomes and autophagy by GSK-3β inhibition not only prevented replicative senescence of the late EPCs but also directed their migration, proliferation and angiogenesis. To conclude, our results demonstrate that lysosome activation and autophagy play a crucial role in blocking the replicative senescence of EPCs and in increasing their endothelial function. Thus, the findings provide an insight towards the treatment of ischemia-associated cardiovascular diseases based on the role of late EPCs.

Identification of CD44 As a RAS-MEK-Regulated Invasion Receptor That Is Overexpressed in Neoplastic Mast Cells and Triggers Disease Expansion in Advanced Systemic Mastocytosis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1955-1955
Author(s):  
Niklas Mueller ◽  
Daniel Wicklein ◽  
Gregor Eisenwort ◽  
Juliana Schwaab ◽  
Mohamad Jawhar ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Research Funding ◽  
Functional Role ◽  
Systemic Mastocytosis ◽  
Surface Expression ◽  
Stem And Progenitor Cells ◽  
Soluble Cd44 ◽  
Baseline Levels ◽  
Dose Dependent

Abstract CD44, also known as Hermes antigen, is a multifunctional invasion receptor that mediates homing and expansion of normal and neoplastic stem- and progenitor cells in various organs including the bone marrow (BM). Mast cells (MC) and their progenitors also express CD44. However, little is known about the impact and regulation of CD44 in neoplastic cells in systemic mastocytosis (SM). We examined the expression, regulation, and functional role of CD44 in neoplastic cells in SM. As assessed by multi-color flow cytometry, CD34+/CD38- stem cells (SC), CD34+/CD38+ progenitor cells (PC), and KIT+/CD34- MC invariably expressed CD44 in all SM variants, including patients with indolent SM (ISM, 11/11), SM with associated hematologic neoplasm (SM-AHN, 7/7), aggressive SM (ASM, 3/3), and MC leukemia (MCL, 8/8). Expression of CD44 on SC, PC, and MC increased significantly with the aggressiveness of SM. Moreover, soluble CD44 levels measured in the sera of patients with SM by ELISA were found to correlate with the WHO type of SM. In particular, significantly higher levels of soluble CD44 were measured in advanced SM compared to ISM, cutaneous mastocytosis (CM), or healthy controls (p<0.05). In addition, all human MC lines examined, including HMC-1.1, HMC-1.2, ROSAKIT WT, ROSAKIT D816V, MCPV-1.1, MCPV-1.2, MCPV-1.3, and MCPV-1.4 expressed cytoplasmic and cell surface CD44. To study the mechanisms underlying CD44 expression on MC, we applied various targeted drugs. Incubation with the demethylating agents decitabine (0.1-5 µM) or 5-azacytidine (0.1-5 µM) for 96 hours resulted in a dose-dependent upregulation of CD44 surface expression compared to baseline levels (100%) in all MC lines examined (decitabine, 5 µM: 210±50% in HMC-1.1, 294±76% in HMC-1.2, 236±56% in ROSAKIT WT, 210±54% in ROSAKIT D816V, 242±47% in MCPV-1.1, 179±23% in MCPV-1.2, 207±17% in MCPV-1.3, and 152±5% in MCPV-1.4 cells, p<0.05; 5-azacytidine, 5 µM: 355±104% in HMC-1.1, 429±105% in HMC-1.2, 412±135% in ROSAKIT WT, 292±136% in ROSAKIT D816V, 365±55% in MCPV-1.1, 345±106% in MCPV-1.2, 325±87% in MCPV-1.3, and 278±38% in MCPV-1.4 cells, p<0.05). In contrast, incubation with the MEK-inhibitor refametinib (RDEA119) (0.1-5 µM) or the STAT5 blocker pimozide (2.5-10 µM) for 48 hours resulted in a dose-dependent downregulation of CD44 surface expression compared to baseline levels (100%) in all MC lines examined (refametinib, 2.5 µM: 71±9% in HMC-1.1, 82±3% in HMC-1.2, 33±13% in ROSAKIT WT, 31±3% in ROSAKIT D816V, 62±6% in MCPV-1.1, 82±13% in MCPV-1.2, 84±5% in MCPV-1.3, and 87±1% in MCPV-1.4 cells, p<0.05; pimozide, 7.5 µM: 59±7% HMC-1.1, 68±3% in HMC-1.2, 62±16% in ROSAKIT WT, and 80±3% in ROSAKIT D816V, 62±5% in MCPV-1.1, 72±4% in MCPV-1.2, 73±4% in MCPV-1.3, and 63±9% in MCPV-1.4 cells, p<0.05). These data suggest that the RAS/MEK pathway and the STAT5 pathway are involved in expression of CD44 in neoplastic MC. In order to confirm this hypothesis we transduced HMC-1.2 cells and ROSAKIT WT cells with KRASWT or oncogenic KRASG12V. In all transduced cell lines, KRAS overexpression resulted in upregulation of CD44 surface expression compared to empty vector (100%) (HMC-1.2: 143±17% with KRASWT, 249±53% with KRASG12V, p<0.05; ROSAKIT WT: 170±13% with KRASWT, 403±64% with KRASG12V, p<0.05). As expected, refametinib was found to suppress RAS-induced CD44 expression in these cells. To study the functional role of CD44 in neoplastic MC, we employed a mouse xenotransplantation model using severe combined immunodeficient (SCID) mice, HMC-1.2 cells, and shRNA against CD44. In this model, the shRNA-induced knock-down of CD44 in HMC-1.2 cells resulted in reduced MC expansion, reduced tumor formation, delayed ulceration, and prolonged survival compared to cells transduced with control shRNA (median survival in the CD44 shRNA group: 110 days vs 97 days in the control group, p<0.05). The formation of lung metastasis, quantified by human Alu-sequence-specific qPCR, was found to be particularly decreased (15-fold) in the CD44 knock-down group compared to control mice. In conclusion, CD44 is expressed in neoplastic MC as well as in neoplastic stem- and progenitor cells in patients with advanced SM. Our data also suggest that CD44 is an important mediator of evolution and of malignant spread of neoplastic MC into various organs in SM. Future studies will show whether CD44 can serve as a therapeutic target in patients with advanced SM. Disclosures Hoermann: Gilead: Research Funding; Novartis: Honoraria; Amgen: Honoraria; Ariad: Honoraria. Sperr:Novartis: Honoraria; Amgen: Honoraria, Research Funding. Arock:Agensys, Inc: Research Funding. Valent:Ariad: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria; Deciphera Pharmaceuticals: Research Funding; Celgene: Honoraria, Research Funding.

Abstract 3139: The microRNA 17-92 Cluster Mediates Sonic Hedgehog-driven Neurogenesis In Ischemic Neural Progenitor Cells

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Xianshuang Liu ◽  
Michael Chopp ◽  
Tao Tang ◽  
Haifa Kassis ◽  
Jennifer Xu ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Sonic Hedgehog ◽  
Functional Role ◽  
Neural Progenitor Cells ◽  
Neural Progenitor ◽  
Control Group ◽  
Western Blots ◽  
Shh Pathway ◽  
Empty Vector

Background: The Sonic hedgehog (Shh) pathway regulates stroke-induced neurogenesis. The present study investigated the functional role of the microRNA 17-92 (miR17-92) cluster in this process. Methods and Results: Analysis of miRNA microarray and real-time RT-PCR revealed that stroke substantially increased levels of individual members of the miR17-92 cluster: miR-18a (1.8±0.3), miR-19a (2.5±0.4), and miR-92a (1.9±0.3) expression in neural progenitor cells (NPCs) harvested from the subventricular zone (SVZ) of ischemic rats (n=6). Overexpression of the miR17-92 cluster in cultured NPCs significantly increased NPC proliferation measured by the number of BrdU positive cells (52±4% vs 28±2% in empty vector, n=3/group, p<0.05). Concurrently, overexpression of the miR17-92 cluster reduced PTEN (phosphatase and tensin homolog), a target of the miR17-92 cluster, protein levels by 70% compared to levels in NPCs transfected with an empty vector. PTEN suppresses cell proliferation. These data suggest that the stroke-upregulated miR17-92 cluster enhances NPC proliferation via downregulation of PTEN. To examine whether Shh regulates miR17-92 cluster expression, NPCs were incubated with recombinant human Shh (rhShh, 100ng/ml). We found that rhShh significantly (p<0.05) increased levels of individual members of the miR17-92 cluster: miR-18a (2.1±0.1), miR-19a (1.3±0.7), miR-19b (1.5±0.6) and miR-92a (1.9±0.8). Blockage of a Shh receptor Smo with cyclopamine suppressed rhShh-increased levels of miR-18a (0.9±0.08), miR-19a (0.7±0.01), miR-19b (0.6±0.05) and miR-92a (0.8±0.04). Attenuation of endogenous Shh in NPCs with siRNA also substantially decreased levels of miR-18a (0.6±0.1), miR-19a (0.4±0.05) and miR-92a (0.6±0.1) compared with levels in NPCs transfected with scrambled siRNA (1.0±0.2, n=3), indicating that Shh regulates miR17-92 expression. MYC is a downstream target of Shh. Western blots showed that stroke increased the protein level of N-MYC 1.8 fold in SVZ tissues and incubation of NPCs with rhShh elevated N-MYC levels by 1.8 fold, which was abrogated by cyclopamine (1.3 fold). N-MYC transduction resulted in significant increases in expression of the primary miR17-92 cluster (2.1±0.3 vs 1.0±0.2 in control group, n=3, p<0.05). These data suggest that the Shh pathway recruits N-MYC to regulate miR17-92 cluster expression in NPCs. Conclusion: Our data suggest a functional role of the miR17-92 cluster in mediating stroke-induced neurogenesis by the SHH/MYC signaling pathway, which provides new insight into molecular mechanisms of stroke-induced neurogenesis.

103. ROLE OF CANDIDATE STEM/PROGENITOR CELLS IN A MOUSE MODEL OF ENDOMETRIAL MENSTRUAL BREAKDOWN AND REPAIR

2009 ◽  
Vol 21 (9) ◽  
pp. 22
Author(s):  
T. J. Kaitu'u-Lino ◽  
L. Ye ◽  
C. E. Gargett
Keyword(s):  
Confocal Microscopy ◽  
Mouse Model ◽  
Progenitor Cells ◽  
Functional Role ◽  
Double Immunofluorescence ◽  
Regenerative Capacity ◽  
Brdu Label ◽  
Nuclear Label ◽  
Human And Mouse

Adult stem/progenitor cells (SPC) identified in human and mouse endometrium may be responsible for its remarkable regenerative capacity (1), however a functional role for SPC in menstruation is yet to be established. This study aimed to identify label retaining cells (LRC) as candidate epithelial SPC involved in the rapid re-epithelisation of the uterine surface in a mouse model; tissue SPCs are quiescent and will retain label (BrdU), while label is diluted out as transit amplifying cells proliferate. Mice were ovariectomised and endometrial breakdown and repair induced, mimicking menstruation in women (2). BrdU (50µg/g) was administered intraperitoneally 8.5 days before endometrial repair. Tissue was collected to assess initial labelling, and following four chase periods prior to and during endometrial repair (n=3-5 animals/group) and immunostained for BrdU. LRC were categorised as minimal (<50% nuclear label), partial (50-75%) and full (100%) and counted in the luminal (LE) and glandular (GE) epithelial compartments for each group. The majority of LE (91.4±1.9%; mean±SEM) and 35±3.8% of GE were initially labelled. During breakdown and repair the percentage of full LE LRC (38±13.1% vs 1.3±1.1%) and partial LE LRC (49.1±4.3% vs 1.8±0.7%) significantly decreased (p≤0.01) whilst minimal LRC significantly increased (12.9±3.5% vs 85.2±4.3%; p≤0.001) indicating dilution of BrdU label as cells proliferated. In contrast full, partial and minimal GE LRC did not significantly change throughout endometrial breakdown and repair. The rapid dilution of BrdU label in the LE suggests that the transit amplifying population are responsible for the rapid proliferation observed, whilst the lack of change of BrdU in the GE suggests that GE may be a source of SPC. Double immunofluorescence and confocal microscopy are currently underway to further characterise the LRC population in this model. This study provides some of the first insights into the contribution of candidate SPC to endometrial repair.

Bone Marrow Endothelial Cell Support of Primitive Hematopoietic Cells

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3573-3573
Author(s):  
Xiaoying Zhou ◽  
Dilani Rosa ◽  
Cynthia Cunningham ◽  
Gregor B. Adams
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Functional Role ◽  
Hematopoietic Cells ◽  
Hematopoietic Progenitor Cells ◽  
Hematopoietic Progenitor ◽  
Hematopoietic Stem ◽  
Vascular Niche

Abstract Hematopoietic stem cells (HSCs) in the bone marrow (BM) reside in specialized microenvironments known as the stem cell niche. Many reports have found the HSCs to be resident next to the endosteal surface of bone where cells of the osteoblastic lineage are a key component of the so-called endosteal niche. However, HSCs have also been found to reside adjacent to sinusoidal blood vessels. These observations have led to the proposal that HSCs in the adult BM may also reside in a vascular niche. However, the functional role of the vascular niche in hematopoiesis remains to be determined. We wished to evaluate the role that BM endothelial cells (BMECs) play in HSC physiology. To examine this we cultured BMEC-enriched cells in vitro, identified by expression of CD31, Tie-2, VE-cadherin and LDL uptake. We compared these cells to spleen derived ECs and BM stromal cells (BMSCs) in their ability to support primitive hematopoietic cells for extended periods in in vitro culture. We found that BMECs were superior in their ability to support the cobblestone area forming cell activity of VEGF-R1+ HSCs than spleen ECs or BMSCs. We also found that the number of cobblestone area cells was markedly reduced when VEGF-R1− HSCs were cultured on any of the supportive cell layers, however this may be due to an intrinsic difference between these cells as a much higher proportion of VEGF-R1+ HSCs were found to be in the G0 phase of the cell cycle than VEGF-R1− cells. To evaluate the supportive role of BMECs, spleen ECs or BMSCs on hematopoietic progenitor cells (HPC) we cultured purified primitive cells on these supportive layers and the total number of colony-forming unit-culture (CFU-C) cells were examined after 4-days or 7-days co-culture with the feeder cells. The results showed that BMECs or spleen ECs can promote the generation of CFU-C from VEGFR1+ HSCs or VEGFR1− HSCs, yet the tot al number of CFU-C produced from VEGFR1+ HSCs was greater than that from VEGFR1- HSCs. However, both of these cell types were able to support the generation of CFU-Cs to a greater degree than BMSCs. To examine the mechanism of enhanced support of VEGF-R1+ HSCs by the BMECs, we performed real-time PCR analysis for the expression of the VEGF-R1 ligands. Both BMECs and spleen ECs were found to express VEGF-A and –B to similar levels, however the expression of placental growth factor was higher in the BMECs. Whether the increased expression of this factor plays a functional role in the support of the HSCs in currently being evaluated. Our findings suggest that the ECs from BM or spleen can promote the proliferation of hematopoietic progenitor cells, while BMECs can maintain the long-term culture of VEGFR1+ HSCs in vitro. The functional relevance of this in vivo is currently being investigated.

473 Functional Role of Definitive Endoderm Marker FOXA2 in Biliary-Committed Progenitor Cells During Cholestatic Liver Injury

2014 ◽  
Vol 146 (5) ◽  
pp. S-912
Author(s):  
Kelly McDaniel ◽  
Yuyan Han ◽  
Shannon Glaser ◽  
Heather L. Francis ◽  
Julie Venter ◽  
...  
Keyword(s):  
Liver Injury ◽  
Progenitor Cells ◽  
Functional Role ◽  
Definitive Endoderm ◽  
Cholestatic Liver Injury
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