scholarly journals PIWIL1 Drives Chemoresistance in Multiple Myeloma by Modulating Mitophagy and the Myeloma Stem Cell Population

2022 ◽  
Vol 11 ◽  
Author(s):  
Yajun Wang ◽  
Lan Yao ◽  
Yao Teng ◽  
Hua Yin ◽  
Qiuling Wu
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Stem Cell ◽  
Cell Population ◽  
Side Population ◽  
Chemotherapeutic Agents ◽  
Stem Cell Population ◽  
Exact Function

As an important member of the Argonaute protein family, PIWI-like protein 1 (PIWIL1) plays a key role in tumor cell viability. However, the exact function of PIWIL1 in multiple myeloma (MM) and the underlying mechanism remain unclear. Here, we revealed that PIWIL1 was highly expressed in myeloma cell lines and newly diagnosed MM patients, and that its expression was notably higher in refractory/relapsed MM patients. PIWIL1 promoted the proliferation of MM cells and conferred resistance to chemotherapeutic agents both in vitro and in vivo. More importantly, PIWIL1 enhanced the formation of autophagosomes, especially mitophagosomes, by disrupting mitochondrial calcium signaling and modulating mitophagy-related canonical PINK1/Parkin pathway protein components. Mitophagy/autophagy inhibitors overcome PIWIL1-induced chemoresistance. In addition, PIWIL1 overexpression increased the proportion of side population (SP) cells and upregulated the expression of the stem cell-associated genes Nanog, OCT4, and SOX2, while its inhibition resulted in opposite effects. Taken together, our findings demonstrated that PIWIL1 induced drug resistance by activating mitophagy and regulating the MM stem cell population. PIWIL1 depletion significantly overcame drug resistance and could be used as a novel therapeutic target for reversing resistance in MM patients.

scholarly journals Actinomycin D downregulates Sox2 and improves survival in preclinical models of recurrent glioblastoma

2020 ◽  
Vol 22 (9) ◽  
pp. 1289-1301 ◽  
Author(s):  
Jessica T Taylor ◽  
Stuart Ellison ◽  
Alina Pandele ◽  
Shaun Wood ◽  
Erica Nathan ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Population ◽  
High Throughput ◽  
Actinomycin D ◽  
Recurrent Glioblastoma ◽  
Stem Cell Population ◽  
Preclinical Models ◽  
Multicellular Spheroids

Abstract Background Glioblastoma (GBM) has been extensively researched over the last few decades, yet despite aggressive multimodal treatment, recurrence is inevitable and second-line treatment options are limited. Here, we demonstrate how high-throughput screening (HTS) in multicellular spheroids can generate physiologically relevant patient chemosensitivity data using patient-derived cells in a rapid and cost-effective manner. Our HTS system identified actinomycin D (ACTD) to be highly cytotoxic over a panel of 12 patient-derived glioma stemlike cell (GSC) lines. ACTD is an antineoplastic antibiotic used in the treatment of childhood cancers. Here, we validate ACTD as a potential repurposed therapeutic for GBM in 3-dimensional GSC cultures and patient-derived xenograft models of recurrent glioblastoma. Methods Twelve patient-derived GSC lines were screened at 10 µM, as multicellular spheroids, in a 384-well serum-free assay with 133 FDA-approved compounds. GSCs were then treated in vitro with ACTD at established half-maximal inhibitory concentrations (IC50). Downregulation of sex determining region Y–box 2 (Sox2), a stem cell transcription factor, was investigated via western blot and through immunohistological assessment of murine brain tissue. Results Treatment with ACTD was shown to significantly reduce tumor growth in 2 recurrent GBM patient-derived models and significantly increased survival. ACTD is also shown to specifically downregulate the expression of Sox2 both in vitro and in vivo. Conclusion These findings indicate that, as predicted by our HTS, ACTD could deplete the cancer stem cell population within the tumor mass, ultimately leading to a delay in tumor progression. Key Points 1. High-throughput chemosensitivity data demonstrated the broad efficacy of actinomycin D, which was validated in 3 preclinical models of glioblastoma. 2. Actinomycin D downregulated Sox2 in vitro and in vivo, indicating that this agent could target the stem cell population of GBM tumors.

Stem cells in mammary health and milk production

2021 ◽  
Vol 16 ◽  
Author(s):  
Ratan K Choudhary ◽  
Fenq-Qi Zhao
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Cell Population ◽  
Adult Stem Cells ◽  
Stem Cell Population ◽  
Mammary Stem ◽  
In Vitro Expansion

: Adult stem cells like mammary and mesenchymal stem cells have received significant attention because these stem cells (SCs) possess therapeutic potential in treating many animal diseases. These cells can be administered in an autologous or allogenic fashion, either freshly isolated from the donor tissue or previously cultured and expanded in vitro. Expansion of adult stem cells is a prerequisite before therapeutic application because sufficient numbers are required in dosage calculation. Stem cells directly and indirectly (by secreting various growth factors and angiogenic factors called secretome) act to repair and regenerate injured tissues. Recent studies on mammary stem cells showed in vivo and in vitro expansion ability by removing the blockage of asymmetrical cell division. Compounds like purine analogs (xanthosine, xanthine, and inosine) or hormones (progesterone and bST) help increase stem cell population by promoting cell division. Such methodology of enhancing stem cells number, either in vivo or in vitro, may help in preclinical studies for translational research like treating diseases like mastitis. The application of mesenchymal stem cells has also been shown to benefit mammary gland health due to the ‘homing’ property of stem cells. In addition to that, the multiple positive effects of stem cell secretome are on mammary tissue healing and killing bacteria is novel in the production of quality milk. This systematic review discusses some of the studies on stem cells that have been useful in increasing the stem cell population and increasing mammary stem/progenitor cells. Finally, we provide insights into how enhancing mammary stem cell population could potentially increase terminally differentiated cells, ultimately leading to more milk production.

scholarly journals Physiological pathway of differentiation of hematopoietic stem cell population into mural cells

2006 ◽  
Vol 203 (4) ◽  
pp. 1055-1065 ◽  
Author(s):  
Yoshihiro Yamada ◽  
Nobuyuki Takakura
Keyword(s):  
Stem Cell ◽  
Blood Vessels ◽  
Hematopoietic Stem Cell ◽  
Cell Population ◽  
Critical Role ◽  
Stem Cell Population ◽  
Hematopoietic Stem ◽  
Mural Cells

Endothelial cells (ECs), which are a major component of blood vessels, have been reported to develop in adulthood from hematopoietic cell populations, especially those of the monocyte lineage. Here we show that mural cells (MCs), another component of blood vessels, develop physiologically during embryogenesis from a hematopoietic stem cell (HSC) population, based on the in vitro culture of HSCs and histological examination of acute myeloid leukemia 1 mutant embryos, which lack HSCs. As in the embryo, HSCs in adult bone marrow differentiate into CD45+CD11b+ cells before differentiating into MCs. Moreover, CD45+CD11b+ cells are composed of two populations, CD11bhigh and CD11blow cells, both of which can differentiate into MCs as well as ECs. Interestingly, in a murine ischemia model, MCs and ECs derived from the CD11blow population had a long-term potential to contribute to the formation of newly developed blood vessels in vivo compared with the CD11high population, which could not. Moreover, injection of the CD11bhigh population induced leaky blood vessels, but the CD11blow population did not. With respect to the permeability of vessels, we found that angiopoietin 1, which is a ligand for Tie2 receptor tyrosine kinase expressed on ECs and is suggested to induce cell adhesion between ECs and MCs, is produced by the CD11blow population and plays a critical role in the formation of nonleaky vessels. These observations suggested that the CD11low cell population serves as a good source of cells for in vivo blood vessel regeneration.

RARα2 Expression Confers Myeloma Stem Cell Features

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5404-5404 ◽  
Author(s):  
Guido J. Tricot ◽  
Ye Yang ◽  
Zhimin Gu ◽  
Hongwei Xu ◽  
Junwei Huang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Drug Resistance ◽  
Stem Cell ◽  
Cell Lines ◽  
Plasma Cells ◽  
Efflux Pump ◽  
Conflicts Of Interest ◽  
Side Population

Abstract Background Despite the major advances in the therapy of MM, many patients ultimately relapse and die of this disease. This is most likely due to the persistence of multiple myeloma stem cells (MMSCs), which survive even after the most intensive treatments and are insensitive to non-transplant therapy. We have previously demonstrated that RARα2 expression increased in CD138 selected plasma cells of relapsed myelomas (MM) and that increased expression was linked to poor prognosis in newly diagnosed MM patients. In this study, we further explore the relationship between RARα2 and MMSCs. Materials and Methods RT-PCR was used to detect RARα2, induced pluripotent stem cell (iPS) gene, Wnt and Hedgehog (Hh) gene expression in MMSCs and bulk cells. Clonogenic formation assays were performed by plating RARα2 over-expressing ARP1 and OCI-MY5 MM cell lines in soft agar, treated with bortezomib, doxorubicin, etoposide, and MK-571. Side population (SP) fraction, ALDH activity and cell apoptosis in MM cells were detected by flow cytometry. Western blot were utilized to dissect RARα2-related signaling pathway. Effect of RARα2 on MM progression in vivo was also analyzed in 5TGM1 myeloma mice. Results Higher expression of RARα2 was identified in the multiple myeloma stem cell (MMSC) fraction. Over-expression of RARα2 in MM cell lines resulted in 1) increased drug-resistance 2) increased clonogenic potential 3) activation of both Wnt and Hedgehog (Hh) pathways 4) increased side population (SP) and aldehyde dehydrogenase1 (ALDH1) levels and 5) increased expression of iPS genes. The opposite effects were seen with RARα2 knockdown. RARα2 induced drug resistance by activating the drug efflux pump gene ABCC3 and anti-apoptotic Bcl-2 family members. Inhibition of Wnt signaling or ABCC3 function could overcome drug resistance in RARα2 over-expressing MM cells. Our In vivo study indicated that targeting Wnt and Hh pathways using CAY10404, cyclopamine or itraconazole could significantly reduce tumor burden and increase survival time in the 5TGM1 mouse model. We confirmed these findings in primary myeloma stem cells. Finally, we showed that primary myelomas with high RARα2 expression possess similar features as myeloma stem cells. Conclusion This study demonstrates that RARα2 plays a crucial role in MMSCs by activating Wnt and Hh pathways, regulating the transcription of iPS genes and conferring drug resistance. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Targeting NSD2-mediated SRC-3 liquid–liquid phase separation sensitizes bortezomib treatment in multiple myeloma

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jing Liu ◽  
Ying Xie ◽  
Jing Guo ◽  
Xin Li ◽  
Jingjing Wang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Phase Separation ◽  
Liquid Phase ◽  
Liquid Phase Separation ◽  
Acquired Drug Resistance ◽  
Bortezomib Treatment ◽  
Liquid Liquid Phase Separation

AbstractDevelopment of chemoresistance is the main reason for failure of clinical management of multiple myeloma (MM), but the genetic and epigenetic aberrations that interact to confer such chemoresistance remains unknown. In the present study, we find that high steroid receptor coactivator-3 (SRC-3) expression is correlated with relapse/refractory and poor outcomes in MM patients treated with bortezomib (BTZ)-based regimens. Furthermore, in immortalized cell lines, high SRC-3 enhances resistance to proteasome inhibitor (PI)-induced apoptosis. Overexpressed histone methyltransferase NSD2 in patients bearing a t(4;14) translocation or in BTZ-resistant MM cells coordinates elevated SRC-3 by enhancing its liquid–liquid phase separation to supranormally modify histone H3 lysine 36 dimethylation (H3K36me2) modifications on promoters of anti-apoptotic genes. Targeting SRC-3 or interference of its interactions with NSD2 using a newly developed inhibitor, SI-2, sensitizes BTZ treatment and overcomes drug resistance both in vitro and in vivo. Taken together, our findings elucidate a previously unrecognized orchestration of SRC-3 and NSD2 in acquired drug resistance of MM and suggest that SI-2 may be efficacious for overcoming drug resistance in MM patients.

Reserve stem cell population in intestinal crypts found to be consistently small by analysis of in vivo clonogenic assays with a biomathematical dynamic model

2018 ◽  
Vol 129 (3) ◽  
pp. 595-599 ◽  
Author(s):  
Emanuel Bahn ◽  
Michelle van Heerden ◽  
John Gueulette ◽  
Jacobus P. Slabbert ◽  
William Shaw ◽  
...  
Keyword(s):  
Stem Cell ◽  
Dynamic Model ◽  
Cell Population ◽  
Stem Cell Population ◽  
Clonogenic Assays

Deacetylation Induced Nuclear Condensation of HP1γ Promotes Multiple Myeloma Drug Resistance

2021 ◽  
Author(s):  
Zhiqiang Liu ◽  
Xin Li ◽  
Sheng Wang ◽  
Ying Xie ◽  
Hongmei Jiang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Dna Damage ◽  
Drug Resistance ◽  
Heterochromatin Protein 1 ◽  
Nuclear Condensation ◽  
Repair Capacity ◽  
Acquired Drug Resistance ◽  
Histone Deacetylase 1

Abstract Acquired chemoresistance to proteasome inhibitors (PIs) is a major obstacle that results in failure to manage patients with multiple myeloma (MM) in the clinic; however, the key regulators and underlying mechanisms are still unclear. In this study, we found that high levels of a chromosomal modifier, heterochromatin protein 1 gamma (HP1γ), are accompanied by a low acetylation level in bortezomib-resistant (BR) MM cells, and aberrant DNA repair capacity is correlated with HP1γ overexpression. Mechanistically, the deacetylation of HP1γ at lysine 5 by histone deacetylase 1 (HDAC1) alleviates HP1γ ubiquitination, and the stabilized HP1γ recruits the mediator of DNA damage checkpoint 1 (MDC1) to induce DNA damage repair. Simultaneously, deacetylation modification and MDC1 recruitment enhance the nuclear condensate of HP1γ, which facilitates the chromatin accessibility of genes governing sensitivity to PIs, such as FOS, JUN and CD40. Thus, targeting HP1γ stability using the HDAC1/2 inhibitor, romidepsin, sensitizes PIs treatment and overcomes drug resistance both in vitro and in vivo. Our findings elucidate a previously unrecognized role of HP1γ in the acquired drug resistance of MM and suggest that targeting HP1γ may be efficacious for overcoming drug resistance in MM patients.

Characterization and in vitro hematopoietic capacity of a very small embryonic like stem cell population isolated from human cord blood

Cytotherapy ◽  
2017 ◽  
Vol 19 (5) ◽  
pp. S77-S78
Author(s):  
E. Gounari ◽  
A. Daniilidis ◽  
I. Koliakou ◽  
N. Tsagias ◽  
K. Kouzi ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cord Blood ◽  
Cell Population ◽  
Stem Cell Population ◽  
Human Cord Blood
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