Small-molecule inhibitors targeting INK4 protein p18INK4C enhance ex vivo expansion of haematopoietic stem cells

Gao, Yingdai; Yang, Peng; Shen, Hongmei; Yu, Hui; Song, Xianmin; Zhang, Liyan; Zhang, Peng; Cheng, Haizi; Xie, Zhaojun; Hao, Sha; Fang, Dong; Ma, Shihui; Ji, Qing; Bartlow, Patrick; Ding, Ye; Wang, Lirong; Liu, Haibin; Li, Yanxin; Cheng, Hui; Miao, Weimin; Yuan, Weiping; Yuan, Youzhong; Cheng, Tao; Xie, Xiang‐Qun

doi:10.1038/ncomms7328

Cited by 48 publications

(51 citation statements)

References 36 publications

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“…However, the significant effect of p18 absence on HSC cannot be solely explained by its classical role in cell cycle regulation, as deletion of p18 did not significantly affect the cell cycle profile of HSCs despite its profound effect on HSC engraftment and reconstitution in recipient mice [49]. Interestingly, our recent work demonstrated a specific role of small molecule inhibitors for p18 protein on HSC expansion, indicating the potential value of targeting p18 for therapeutic expansion of HSC [49,51].…”

Section: P18mentioning

confidence: 99%

“…Deficiency of p18 results in an expansion of stem and progenitor cells, which show a competitive advantage in serial bone marrow transplantation assays compared with that of normal controls [47,48]. Among all the CKIs, p18 appears to have the strongest impact on HSC self-renewal in mice [49]. Regarding its mechanism, it has been proposed that HSCs have a shorter G1 phase due to a lower cyclin D/ CDK4 threshold activity.…”

Section: P18mentioning

confidence: 99%

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Cell cycle regulation of hematopoietic stem or progenitor cells

2016

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Section: P18mentioning

confidence: 99%

Section: P18mentioning

confidence: 99%

Cell cycle regulation of hematopoietic stem or progenitor cells

2016

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“…60 Cell cycle regulator (CKI) also plays a vital role in stem cell manipulation; two inhibitors of CKI p18 INK4C , P18IN003 and P18IN011, are known to induce HSC expansion. 19 Other molecules that induce HSC expansion are advancing through clinical trials, including TEPA (copper chelate), 73 SR1 (AhR antagonist), 74 and Nicord (SIRT1 inhibitor). 75 These compounds have completed phase I/II and are now in phase II/III multicenter clinical trials 76 (Figure 3D).…”

Section: Resultsmentioning

confidence: 99%

“…The number of published studies focusing on stem cell-related signaling pathways and small molecule modulators is steadily increasing, while generating the experimental data required to find, associate, and validate reported active compounds can be slow and challenging. 2,19 …”

Section: Introductionmentioning

confidence: 99%

StemCellCKB: An Integrated Stem Cell-Specific Chemogenomics KnowledgeBase for Target Identification and Systems-Pharmacology Research

Wang

Feng

Cheng

et al. 2016

J. Chem. Inf. Model.

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Given the capacity of self-renewal and multilineage differentiation, stem cells are promising sources for use in regenerative medicines as well as in the clinical treatment of certain hematological malignancies and degenerative diseases. Complex networks of cellular signaling pathways largely determine stem cell fate and function. Small molecules that modulate these pathways can provide important biological and pharmacological insights. However, it is still challenging to identify the specific protein targets of these compounds, to explore the changes in stem cell phenotypes induced by compound treatment and to ascertain compound mechanisms of action. To facilitate stem cell related small molecule study and provide a better understanding of the associated signaling pathways, we have constructed a comprehensive domain-specific chemogenomics resource, called StemCellCKB (http://www.cbligand.org/StemCellCKB/). This new cloud-computing platform describes the chemical molecules, genes, proteins, and signaling pathways implicated in stem cell regulation. StemCellCKB is also implemented with web applications designed specifically to aid in the identification of stem cell relevant protein targets, including TargetHunter, a machine-learning algorithm for predicting small molecule targets based on molecular fingerprints, and HTDocking, a high-throughput docking module for target prediction and systems-pharmacology analyses. We have systematically tested StemCellCKB to verify data integrity. Target-prediction accuracy has also been validated against the reported known target/compound associations. This proof-of-concept example demonstrates that StemCellCKB can (1) accurately predict the macromolecular targets of existing stem cell modulators and (2) identify novel small molecules capable of probing stem cell signaling mechanisms, for use in systems-pharmacology studies. StemCellCKB facilitates the exploration and exchange of stem cell chemogenomics data among members of the broader research community.

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“…p18 [144] as a speciic inhibitor of cyclin-dependent kinase (CDK) is a potential direct target of cell cycle regulation. Two small-molecule compounds P18IN003 and P18IN011 were identiied in this study as being able to enhance the proliferation of mouse HSC cells and increase the reconstitution to bone marrow by at least threefold.…”

Section: Further Cytokine and Small Molecule Addition To Expand Umentioning

confidence: 99%

Umbilical Cord Blood Hematopoietic Stem and Progenitor Cell Expansion for Therapeutic Use

Watt¹,

Hua²

2017

Umbilical Cord Blood Banking for Clinical Application and Regenerative Medicine

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Hematopoietic stem cell transplantation (HSCT) is a potentially curative therapy for severe hematological malignancies and other severe disorders of the blood, immune system, and bone marrow. It is the most successful regenerative therapy to date, with 2013 marking the one millionth HSCT and the 25th anniversary of the irst umbilical cord blood (UCB) HSCT. UCB has most often been used for allogeneic HSCT when a matched bone marrow or peripheral blood donor is unavailable. Recently, novel genome editing technologies to correct inherited gene disorders or to modulate biomarkers/ receptors on HSC and the potential use of HSCT for a variety of other nonmalignant conditions have led to a surge of interest in autologous HSCT, with the HSC source depending on the condition to be treated. UCB HSCs may be used to generate red blood cells, granulocytes, or platelets ex vivo for transfusion into diicult-to-transfuse patients. Alternatively, UCB may be reprogrammed to induced pluripotent stem cells or used to generate cell lines, which can then be diferentiated into diferent cell lineages for transfusion or used as diagnostic reagents. Disadvantages of UCB are its restricted cell numbers and delayed hematological engraftment. Here, UCB HSC expansion/ manipulation ex vivo and clinical applications are addressed.

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Small-molecule inhibitors targeting INK4 protein p18INK4C enhance ex vivo expansion of haematopoietic stem cells

Cited by 48 publications

References 36 publications

Cell cycle regulation of hematopoietic stem or progenitor cells

Cell cycle regulation of hematopoietic stem or progenitor cells

StemCellCKB: An Integrated Stem Cell-Specific Chemogenomics KnowledgeBase for Target Identification and Systems-Pharmacology Research

Umbilical Cord Blood Hematopoietic Stem and Progenitor Cell Expansion for Therapeutic Use

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