Regulators of pluripotency and their implications in regenerative medicine

El-Badawy, Ahmed; El‐Badri, Nagwa

doi:10.2147/sccaa.s80157

Cited by 16 publications

(11 citation statements)

References 128 publications

(153 reference statements)

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“…Stem cell therapy represents a highly promising new modality of treatment for advanced diabetes. However, many concerns about the type of stem cells, the transplantation procedure, and long-term recovery remain to be addressed [ 6 ]. Numerous in vivo animal studies demonstrated the potential advantages of using stem cells to treat DM.…”

Section: Introductionmentioning

confidence: 99%

Clinical Efficacy of Stem Cell Therapy for Diabetes Mellitus: A Meta-Analysis

2016

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BackgroundStem cell therapy is a promising therapeutic modality for advanced diabetes mellitus (DM). This study presents a meta-analysis of relevant clinical trials to determine the efficacy of stem cell therapy in DM. We aim to critically evaluate and synthesize clinical evidence on the safety and efficiency of different types of stem cell therapy for both T1DM and T2DM.Methods and FindingsWe pooled participant-level data from twenty-two eligible clinical trials that satisfied our inclusion criteria, with a total of 524 patients. There were significant differences in the outcome based on the type and source of the infused cells. Out of all T1DM patients who received CD34+ hematopoietic stem cell (HSC) infusion, 58.9% became insulin independent for a mean period of 16 months, whereas the results were uniformly negative in patients who received umbilical cord blood (UCB). Infusion of umbilical cord mesenchymal stem cells (UC-MSCs) provided significantly beneficial outcome in T1DM, when compared to bone-marrow mesenchymal stem cells (BM-MSCs) (P<0.0001 and P = 0.1557). Administration of stem cell therapy early after DM diagnosis was more effective than intervention at later stages (relative risk = 2.0, P = 0.0008). Adverse effects were observed in only 21.72% of both T1DM and T2DM stem cell recipients with no reported mortality. Out of all poor responders, 79.5% were diagnosed with diabetic ketoacidosis.ConclusionsStem cell transplantation can represent a safe and effective treatment for selected patients with DM. In this cohort of trials, the best therapeutic outcome was achieved with CD34+ HSC therapy for T1DM, while the poorest outcome was observed with HUCB for T1DM. Diabetic ketoacidosis impedes therapeutic efficacy.

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Section: Introductionmentioning

confidence: 99%

Clinical Efficacy of Stem Cell Therapy for Diabetes Mellitus: A Meta-Analysis

2016

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“…Cancer progression seems to be mediated by a subgroup of these cells, mesenchymal stem cells (MSCs). MSCs are multipotent cells capable of differentiating into numerous cell types, including adipocytes, osteoblasts, chondrocytes, fibroblasts, and perivascular and vascular structures [ 2 ]. In addition to their high regenerative capacities [ 3 , 4 ], MSCs have also been reported to be among the cells recruited in large numbers to the stroma of developing tumors [ 5 – 8 ] and subsequently have important microenvironmental roles in modulating tumor progression and drug sensitivity [ 9 – 11 ].…”

Section: Introductionmentioning

confidence: 99%

Cancer cell-soluble factors reprogram mesenchymal stromal cells to slow cycling, chemoresistant cells with a more stem-like state

et al. 2017

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BackgroundMesenchymal stem cells (MSCs) play different roles in modulating tumor progression, growth, and metastasis. MSCs are recruited to the tumor site in large numbers and subsequently have an important microenvironmental role in modulating tumor progression and drug sensitivity. However, the effect of the tumor microenvironment on MSC plasticity remains poorly understood. Herein, we report a paracrine effect of cancer cells, in which they secrete soluble factors that promote a more stem-like state in bone marrow mesenchymal stem cells (BM-MSCs).MethodsThe effect of soluble factors secreted from MCF7, Hela, and HepG2 cancer cell lines on BM-MSCs was assessed using a Transwell indirect coculture system. After 5 days of coculture, BM-MSCs were characterized by flow cytometry for surface marker expression, by qPCR for gene expression profile, and by confocal immunofluorescence for marker expression. We then measured the sensitivity of cocultured BM-MSCs to chemotherapeutic agents, their cell cycle profile, and their response to DNA damage. The sphere formation, invasive properties, and in-vivo performance of BM-MSCs after coculture with cancer cells were also measured.ResultsIndirect coculture of cancer cells and BM-MSCs, without direct cell contact, generated slow cycling, chemoresistant spheroid stem cells that highly expressed markers of pluripotency, cancer cells, and cancer stem cells (CSCs). They also displayed properties of a side population and enhanced sphere formation in culture. Accordingly, these cells were termed cancer-induced stem cells (CiSCs). CiSCs showed a more mesenchymal phenotype that was further augmented upon TGF-β stimulation and demonstrated a high expression of the β-catenin pathway and ALDH1A1.ConclusionsThese findings demonstrate that MSCs, recruited to the tumor microenvironment in large numbers, may display cellular plasticity, acquire a more stem-like state, and acquire some properties of CSCs upon exposure to cancer cell-secreted factors. These acquired characteristics may contribute to tumor progression, survival, and metastasis. Our findings provide new insights into the interactions between MSCs and cancer cells, with the potential to identify novel molecular targets for cancer therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-017-0709-9) contains supplementary material, which is available to authorized users.

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“…Telomerase and its core component hTERT are critical for stem cell compartment integrity ( El-Badawy and El-Badri, 2015 ). Normal adult stem cells are known to have the longest telomeres in a given tissue, which is mediated by the upregulation of hTERT ( Flores et al, 2006 ; Hiyama and Hiyama, 2007 ).…”

Section: Discussionmentioning

confidence: 99%

Telomerase reverse transcriptase coordinates with the epithelial-to-mesenchymal transition through a feedback loop to define properties of breast cancer stem cells

et al. 2018

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Telomerase and its core component, telomerase reverse transcriptase (hTERT), are critical for stem cell compartment integrity. Normal adult stem cells have the longest telomeres in a given tissue, a property mediated by high hTERT expression and high telomerase enzymatic activity. In contrast, cancer stem cells (CSCs) have short telomeres despite high expression of hTERT, indicating that the role of hTERT in CSCs is not limited to telomere elongation and/or maintenance. The function of hTERT in CSCs remains poorly understood. Here, we knocked down hTERT expression in CSCs and observed a morphological shift to a more epithelial phenotype, suggesting a role for hTERT in the epithelial-to-mesenchymal transition (EMT) of CSCs. Therefore, in this study, we systematically explored the relationship between hTERT and EMT and identified a reciprocal, bi-directional feedback loop between hTERT and EMT in CSCs. We found that hTERT expression is mutually exclusive to the mesenchymal phenotype and that, reciprocally, loss of the mesenchymal phenotype represses hTERT expression. We also showed that hTERT plays a critical role in the expression of key CSC markers and nuclear β-catenin localization, increases the percentage of cells with side-population properties, and upregulates the CD133 expression. hTERT also promotes chemoresistance properties, tumorsphere formation and other important functional CSC properties. Subsequently, hTERT knockdown leads to the loss of the above advantages, indicating a loss of CSC properties. Our findings suggest that targeting hTERT might improve CSCs elimination by transitioning them from the aggressive mesenchymal state to a more steady epithelial state, thereby preventing cancer progression.

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Regulators of pluripotency and their implications in regenerative medicine

Cited by 16 publications

References 128 publications

Clinical Efficacy of Stem Cell Therapy for Diabetes Mellitus: A Meta-Analysis

Clinical Efficacy of Stem Cell Therapy for Diabetes Mellitus: A Meta-Analysis

Cancer cell-soluble factors reprogram mesenchymal stromal cells to slow cycling, chemoresistant cells with a more stem-like state

Telomerase reverse transcriptase coordinates with the epithelial-to-mesenchymal transition through a feedback loop to define properties of breast cancer stem cells

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