Abstract 13831: Atrial and Ventricular Cardiac Stem Cells From the Same Heart Exhibit Differential Functional Characteristics for Cardiac Regeneration but Are Superior to the Endothelial Progenitor Cells From the Same Patient

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Parul Dixit ◽  
Hayden Donnelly ◽  
Midori Edamatsu ◽  
Ivor Galvin ◽  
Richard Bunton ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Death ◽  
Progenitor Cells ◽  
Wound Closure ◽  
Apoptotic Cell ◽  
Cardiac Regeneration ◽  
Cardiac Stem Cells ◽  
Cell Type ◽  
Functional Characteristics ◽  
Scratch Assay

Introduction: Deciding the best cell type for cardiac regeneration remains a challenge, however, no studies have directly compared the functional efficacy of cardiac stem cells (CSCs) with extra- cardiac SCs isolated from the same patient. Objective: To compare the functional characteristics of endothelial progenitor cells (EPCs), right atrial (RAA) CSCs and left ventricular (LV) CSCs isolated from the same patients. Methods and Results: Flow-cytometry analysis of CSCs (n=12 patients) revealed higher expression of CD90 (involved in cell adhesion and migration) in RAA CSCs (CD90 & CD105 ++ve cells: 71±15% in RAA vs. 47±27% in LV, P<0.05). However, scratch assay showed superior wound closure in LV CSCs (80±10% in LV vs. 60±5% in RAA, P<0.05) suggesting that LV CSCs have a better migration potential. Moreover, the expansion properties of RAA CSCs were better than LV CSCs in terms of higher cumulative population doublings in culture. To simulate in vivo ischemic environment, cells were subjected to hypoxia (1% O2) and serum starvation for 3 days. RAA and LV CSCs exhibited similar pattern of resistance to apoptotic cell death (evaluated as percentage of annexin +ve cells, n=5) and proliferation under hypoxia. Interestingly, EPCs exhibited highest resistance to apoptotic cell death, but they also showed the lowest proliferation under hypoxia (P<0.05). Secretion of paracrine and pro-angiogenic factors have been thought to be most important mechanisms behind cardiac regeneration. Therefore, to compare the paracrine angiogenic and wound healing potential, HUVECs were cultured in culture supernatant (CS) from all the 3 cell types. RAA-CS showed the highest increase in tube formation capacity (P<0.05, n=6), while the scratch assay showed comparable wound closure with both LV and RAA CS (67.56 ± 7.36% and 70.02 ± 5.70%, n=5), but was lowest in EPC CS (54±7%). The secretion of the angiogenic growth factor VEGF-A (n=5) was lowest in EPCs (0.36± 0.20 ng/mL) and comparable between RAA (3.44±1.94 ng/mL) and LV CSCs (4.33± 1.57 ng/mL). Conclusion: Stem cells from different regions exhibit differential functional characteristics within the same patient. The selection of the best cell type should therefore be influenced by the nature of the injury and the type of effect desired.

Presenilin-1 regulates neuronal differentiation during neurogenesis

Development ◽  
2000 ◽  
Vol 127 (12) ◽  
pp. 2593-2606 ◽  
Author(s):  
M. Handler ◽  
X. Yang ◽  
J. Shen
Keyword(s):  
Cell Death ◽  
Progenitor Cells ◽  
Neuronal Differentiation ◽  
Cell Fate ◽  
Neural Progenitor Cells ◽  
Apoptotic Cell ◽  
Ventricular Zone ◽  
Neural Progenitor ◽  
Apoptotic Cell Death ◽  
Presenilin 1

Mutations in Presenilin-1 (PS1) are a major cause of familial Alzheimer's disease. Our previous studies showed that PS1 is required for murine neural development. Here we report that lack of PS1 leads to premature differentiation of neural progenitor cells, indicating a role for PS1 in a cell fate decision between postmitotic neurons and neural progenitor cells. Neural proliferation and apoptotic cell death during neurogenesis are unaltered in PS1(−/−) mice, suggesting that the reduction in the neural progenitor cells observed in the PS1(−/−) brain is due to premature differentiation of progenitor cells, rather than to increased apoptotic cell death or decreased cell proliferation. In addition, the premature neuronal differentiation in the PS1(−/−) brain is associated with aberrant neuronal migration and disorganization of the laminar architecture of the developing cerebral hemisphere. In the ventricular zone of PS1(−/−) mice, expression of the Notch1 downstream effector gene Hes5 is reduced and expression of the Notch1 ligand Dll1 is elevated, whereas expression of Notch1 is unchanged. The level of Dll1 transcripts is also increased in the presomitic mesoderm of PS1(−/−) embryos, while the level of Notch1 transcripts is unchanged, in contrast to a previous report (Wong et al., 1997, Nature 387, 288–292). These results provide direct evidence that PS1 controls neuronal differentiation in association with the downregulation of Notch signalling during neurogenesis.

scholarly journals Nicotinic Receptor-Induced Apoptotic Cell Death of Hippocampal Progenitor Cells

1998 ◽  
Vol 18 (17) ◽  
pp. 6871-6881 ◽  
Author(s):  
Francois Berger ◽  
Fred H. Gage ◽  
Sukumar Vijayaraghavan
Keyword(s):  
Cell Death ◽  
Progenitor Cells ◽  
Nicotinic Receptor ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death

Evasion of Necroptosis and Inflammasome Activation Promotes Myeloid Leukemogenesis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2856-2856
Author(s):  
Ulrike Höckendorf ◽  
Yabal Monica ◽  
Christian Peschel ◽  
Philipp J. Jost
Keyword(s):  
Stem Cells ◽  
Cell Death ◽  
Hematopoietic Stem Cells ◽  
Progenitor Cells ◽  
Protein Level ◽  
Inflammatory Cell ◽  
Leukemic Cells ◽  
Inflammasome Activation ◽  
Short Term ◽  
Hematopoietic Stem

Abstract Acute myeloid leukemia (AML) is a heterogeneous group of hematopoietic neoplasms driven partly by the loss of differentiation and theblockade of cell death. AML is sustained by leukemia-initiating cells (LICs) that arise from pre-leukemic hematopoietic stem and progenitor cells (HSPCs) that carry genetic alterations being selected for during leukemogenesis. The resistance of LICs to standard chemotherapies presents a major clinical challenge as they eventually cause disease relapse and death. Understanding the mechanisms of LIC resistance to undergoing cell death is therefore critical for a curative therapy of AML. While the regulatory factors that maintain HSPC proliferation and differentiation under normal conditions are well understood, significantly less is known about how LIC fate is regulated. As many hematopoietic disorders are characterized by the overproduction of pro-inflammatory cytokines, we hypothesized that necroptosis controlled cytokine secretion and inflammatory cell death might influence AML development. We therefore addressed the role of MLKL and XIAP in AML and tested whether deletion of Mlkl or Xiap would affect disease progression. Here we show that MLKL limits oncogene-mediated leukemogenesis by promoting the inflammatory cell death of common myeloid progenitors (CMPs) and short-term hematopoietic stem cells (HSCs) in experimental mice. Upon oncogenic stress MLKL-dependent necroptosis and subsequent inflammasome activation were triggered, promoting the production of IL-1β, a potent stimulator of HSPC differentiation and maturation, thus, suppressing the emergence of LICs and limiting leukemogenesis. In a murine bone marrow transplantation model of AML the absence of MLKL accelerated AML development significantly. The enhanced disease was due to the expansion of common myeloid progenitors (CMPs) and short-term hematopoietic stem cells (ST-HSCs), being the cellular compartments to contain LICs. The survival advantage of Mlkl-/- HSPCs became apparent in colony-forming assays and liquid cultures specifically within the CMP and ST-HSC compartments. Sorted ST-HSCs from Mlkl-/- produced more GEMM colonies than WT, the colony type harboring the multipotential myeloid progenitor cells, and both ST-HSCs and CMPs retained significantly more lineage-negative cells in liquid culture. In addition, Mlkl-/- colonies showed a reduction in propidium iodide (PI)-positive dead cells compared with WT colonies. Importantly, WT cells showed caspase activation and produced substantial amounts of the inflammatory cytokine IL-1β which was severely blunted by Mlkl deficiency. We also observed reduced expression of MLKL in leukemic cells on both mRNA and protein level, implying that suppression of cell death was beneficial for the survival of LICs. In contrast, deletion of Xiap did not alter survival or differentiation of leukemic cells when compared with WT cells. Furthermore, XIAP was not differentially expressed on mRNA or protein level compared with WT, indicating that XIAP does not play a critical role in leukemogenesis. In agreement with the murine data, gene expression analysis from primary leukemia cells from two large patient cohorts newly diagnosed with AML showed significantly lower expression of MLKL, but not XIAP, in a variety of AML subtypes compared to healthy controls. Overall, our data demonstrate a key role for MLKL-mediated cell death and activation of the inflammasome in AML and represents a novel tumor-suppressive mechanism. Disclosures Peschel: MophoSys: Honoraria.

Harnessing endogenous intra- and extra-cardiac stem cells for cardiac regeneration – hope or hype?

2009 ◽  
Vol 6 (4) ◽  
pp. 127-133 ◽  
Author(s):  
Sunny Sun-Kin Chan ◽  
Ying-Zhang Shueh ◽  
Yen-Wen Liu ◽  
Patrick C.H. Hsieh
Keyword(s):  
Stem Cells ◽  
Cardiac Regeneration ◽  
Cardiac Stem Cells

Medical imaging for cardiac regeneration using resident cardiac stem cells

2013 ◽  
Vol 5 (5) ◽  
pp. 477-486
Author(s):  
Sung Hyun Choi ◽  
So Young Yoo ◽  
Sae Mi Yoo ◽  
Kyeong Been Lee ◽  
Sang Hong Baek ◽  
...  
Keyword(s):  
Stem Cells ◽  
Medical Imaging ◽  
Cardiac Regeneration ◽  
Cardiac Stem Cells

scholarly journals Rapid and selective death of leukemia stem and progenitor cells induced by the compound 4-benzyl, 2-methyl, 1,2,4-thiadiazolidine, 3,5 dione (TDZD-8)

Blood ◽  
2007 ◽  
Vol 110 (13) ◽  
pp. 4436-4444 ◽  
Author(s):  
Monica L. Guzman ◽  
Xiaojie Li ◽  
Cheryl A. Corbett ◽  
Randall M. Rossi ◽  
Timothy Bushnell ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Death ◽  
Progenitor Cells ◽  
Lymphoblastic Leukemia ◽  
Blast Crisis ◽  
Membrane Integrity ◽  
Hematopoietic Stem ◽  
Rapid Induction ◽  
Stem And Progenitor Cells

Leukemia is thought to arise from malignant stem cells, which have been described for acute and chronic myeloid leukemia (AML and CML) and for acute lymphoblastic leukemia (ALL). Leukemia stem cells (LSCs) are relatively resistant to current chemotherapy and likely contribute to disease relapse and progression. Consequently, the identification of drugs that can efficiently eradicate LSCs is an important priority. In the present study, we investigated the antileukemia activity of the compound TDZD-8. Analysis of primary AML, blast crisis CML (bcCML), ALL, and chronic lymphoblastic leukemia (CLL) specimens showed rapid induction of cell death upon treatment with TDZD-8. In addition, for myeloid leukemias, cytotoxicity was observed for phenotypically primitive cells, in vitro colony-forming progenitors, and LSCs as defined by xenotransplantation assays. In contrast, no significant toxicity was observed for normal hematopoietic stem and progenitor cells. Notably, cell death was frequently evident within 2 hours or less of TDZD-8 exposure. Cellular and molecular studies indicate that the mechanism by which TDZD-8 induces cell death involves rapid loss of membrane integrity, depletion of free thiols, and inhibition of both the PKC and FLT3 signaling pathways. We conclude that TDZD-8 uses a unique and previously unknown mechanism to rapidly target leukemia cells, including malignant stem and progenitor populations.

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