|
1
|
Borlongan MC, Rodriguez T, Putthanbut N, Wang H, Lee JY. Modeling of cancer stem cells and the tumor microenvironment Via NT2/D1 cells to probe pathology and treatment for cancer and beyond. Discov Oncol 2025; 16:605. [PMID: 40272656 PMCID: PMC12022208 DOI: 10.1007/s12672-025-02158-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Accepted: 03/17/2025] [Indexed: 04/27/2025] Open
Abstract
INTRODUCTION Unique from the other tumor cells, tumorigenic cancer stem cells (CSCs) manifest as a subpopulation of cells within the tumor that exhibit genetic and phenotypic features and signaling processes, which escape traditional anti-oncogenic treatments, thereby triggering metastases and relapses of cancers. Critical to cancer biology is the crosstalk between CSCs and tumor microenvironment (TME), implicating a CSC-based cancer immunotherapy. Cognizant of CSCs' significant role in cancer pathology and treatment, finding a biological model that recapitulates CSCs and TME may allow a better understanding of tumor onset and progression for testing CSC-based therapies. In this review paper, we examined the CSC and TME characteristics of the human embryonal carcinoma NTERA-2 clonal cell line called NTERA-2 cl.D1 or NT2/D1 cells and discussed their potential utility for research and development of treatments for cancer and central nervous system (CNS) disorders. METHODS To probe our hypotheses that NT2/D1 cells display CSC and TME properties key to tumor development, which can serve as a screening platform to test cancer and CNS therapeutics, we conducted a literature review over a 10-year period (2014-2024), focusing on PUBMED and Science Direct published articles on cellular models of cancer, with emphasis on milestone research discoveries on NT2/D1 cells relevant to CSCs and TME. We categorized the studies under pre-clinical and clinical investigations in supporting the existence of CSC and TME features in NT2/D1 cells and providing a laboratory-to-clinic translational basis for cancer and CNS therapeutics. CONCLUSIONS NT2/D1 cells stand as a feasible biological model that recapitulates the crosstalk of CSCs and TME, which may critically contribute to our understanding of cancer and CNS biology and therapeutics. Designing therapeutics against CSCs' distinct self-renewal and differentiation capacities within the TME opens new avenues for treating cancers and CNS disorders.
Collapse
Affiliation(s)
- Mia C Borlongan
- California Northstate University College of Medicine, Elk Grove, CA, 95757, USA
| | - Thomas Rodriguez
- Loma Linda University School of Medicine, Loma Linda, CA, 92354, USA
| | - Napasiri Putthanbut
- Center of Aging and Brain Repair, Department of Neurosurgery, University of South Florida, Tampa, FL, 33612, USA
- Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Hongbin Wang
- California Northstate University College of Pharmacy, Elk Grove, CA, 95757, USA
| | - Jea-Young Lee
- Center of Aging and Brain Repair, Department of Neurosurgery, University of South Florida, Tampa, FL, 33612, USA.
| |
Collapse
|
|
2
|
Merchant S, Paul A, Reyes A, Cassidy D, Leach A, Kim D, Muh S, Grabowski G, Hoxhaj G, Zhao Z, Morrison SJ. Different effects of fatty acid oxidation on hematopoietic stem cells based on age and diet. Cell Stem Cell 2025; 32:263-275.e5. [PMID: 39708796 DOI: 10.1016/j.stem.2024.11.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Revised: 09/19/2024] [Accepted: 11/25/2024] [Indexed: 12/23/2024]
Abstract
Fatty acid oxidation is of uncertain importance in most stem cells. We show by 14C-palmitate tracing and metabolomic analysis that hematopoietic stem/progenitor cells (HSPCs) engage in long-chain fatty acid oxidation that depends upon carnitine palmitoyltransferase 1a (CPT1a) and hydroxyacyl-CoA dehydrogenase (HADHA) enzymes. CPT1a or HADHA deficiency had little or no effect on HSPCs or hematopoiesis in young adult mice. Young HSPCs had the plasticity to oxidize other substrates, including glutamine, and compensated for loss of fatty acid oxidation by decreasing pyruvate dehydrogenase phosphorylation, which should increase function. This metabolic plasticity declined as mice aged, when CPT1a or HADHA deficiency altered hematopoiesis and impaired hematopoietic stem cell (HSC) function upon serial transplantation. A high-fat diet increased fatty acid oxidation and reduced HSC function. This was rescued by CPT1a or HADHA deficiency, demonstrating that increased fatty acid oxidation can undermine HSC function. Long-chain fatty acid oxidation is thus dispensable in young HSCs but necessary during aging and deleterious with a high-fat diet.
Collapse
Affiliation(s)
- Salma Merchant
- Children's Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Animesh Paul
- Children's Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Amanda Reyes
- Children's Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Daniel Cassidy
- Children's Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Ashley Leach
- Children's Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Dohun Kim
- Children's Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Sarah Muh
- Children's Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Gerik Grabowski
- Children's Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Gerta Hoxhaj
- Children's Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Zhiyu Zhao
- Children's Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Sean J Morrison
- Children's Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
| |
Collapse
|
|
3
|
Liu B, Zhang X, Zhou Y, Liu H, Wang Z, Fu Y, Gao Q, Cheng X, Sun Q, Ju Z. USP4 regulates ribosome biogenesis and protein synthesis for hematopoietic stem cell regeneration and leukemia progression. Leukemia 2024; 38:2466-2478. [PMID: 39266638 DOI: 10.1038/s41375-024-02338-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 06/28/2024] [Accepted: 07/02/2024] [Indexed: 09/14/2024]
Abstract
Enhanced ribosome biogenesis and protein synthesis are required for cell proliferation. During hematopoietic regeneration, hematopoietic stem cells (HSCs) proliferate rapidly to replenish the hematopoietic system. How HSCs respond and regulate ribosome biogenesis and protein synthesis during regeneration remains unclear. Here, we analyzed the expression of a series of ubiquitin-specific-proteases (USPs) during HSC regeneration. We found USP4 expression is significantly increased in proliferating HSCs. Further functional and mechanistic investigations revealed a crucial regulatory function of USP4 in HSC regeneration and leukemia progression by modulating ribosome biogenesis and protein synthesis. USP4 deubiquitinates and stabilizes PES1 to facilitate ribosome biogenesis and protein synthesis in proliferative HSCs and leukemic cells. Usp4 deletion significantly decreases protein synthesis, proliferation and reconstitution capacity of HSCs. Usp4 inhibition suppresses ribosome biogenesis and proliferation of leukemic cells, and prolongs the survival of AML (Acute myeloid leukemia) mice. These findings provide a new insight into the response mechanism of ribosome biogenesis and protein synthesis in HSCs, and their contribution to leukemia progression.
Collapse
Affiliation(s)
- Bo Liu
- Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China.
| | - Xianli Zhang
- Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China
| | - Yuanyuan Zhou
- Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China
| | - Haiping Liu
- Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China
| | - Zhenkun Wang
- Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China
| | - Yuting Fu
- Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China
| | - Qiongdan Gao
- Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China
| | - Xiang Cheng
- Department of Hematology, Children's Hospital, Capital Institute of Pediatrics, 100020, Beijing, China
| | - Qingyuan Sun
- Fertility Preservation Lab, Guangdong-Hong Kong Metabolism and Reproduction Joint Laboratory, Reproductive Medicine Center, Guangdong Second Provincial General Hospital, Guangzhou, 510317, China
| | - Zhenyu Ju
- Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China.
| |
Collapse
|
|
4
|
Özgüldez HÖ, Bulut-Karslioğlu A. Dormancy, Quiescence, and Diapause: Savings Accounts for Life. Annu Rev Cell Dev Biol 2024; 40:25-49. [PMID: 38985838 DOI: 10.1146/annurev-cellbio-112122-022528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/12/2024]
Abstract
Life on Earth has been through numerous challenges over eons and, one way or another, has always triumphed. From mass extinctions to more daily plights to find food, unpredictability is everywhere. The adaptability of life-forms to ever-changing environments is the key that confers life's robustness. Adaptability has become synonymous with Darwinian evolution mediated by heritable genetic changes. The extreme gene-centric view, while being of central significance, at times has clouded our appreciation of the cell as a self-regulating entity informed of, and informing, the genetic data. An essential element that powers adaptability is the ability to regulate cell growth. In this review, we provide an extensive overview of growth regulation spanning species, tissues, and regulatory mechanisms. We aim to highlight the commonalities, as well as differences, of these phenomena and their molecular regulators. Finally, we curate open questions and areas for further exploration.
Collapse
Affiliation(s)
- Hatice Özge Özgüldez
- Stem Cell Chromatin Group, Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany;
| | - Aydan Bulut-Karslioğlu
- Stem Cell Chromatin Group, Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany;
| |
Collapse
|
|
5
|
Wang X, Yao F, Yang L, Han D, Zeng Y, Huang Z, Yang C, Lin B, Chen X. Macrophage extracellular vesicle-packaged miR-23a-3p impairs maintenance and angiogenic capacity of human endothelial progenitor cells in neonatal hyperoxia-induced lung injury. Stem Cell Res Ther 2024; 15:295. [PMID: 39256862 PMCID: PMC11389047 DOI: 10.1186/s13287-024-03920-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 09/02/2024] [Indexed: 09/12/2024] Open
Abstract
BACKGROUND Premature infants requiring mechanical ventilation and supplemental oxygen for respiratory support are at increased risk for bronchopulmonary dysplasia (BPD), wherein inflammation have been proposed as a driver of hyperoxia-induced injuries, including persistent loss of endothelial progenitor cells (EPCs), impaired vascularization and eventual alveolar simplification in BPD lungs. However, the underlying mechanisms linking these phenomena remain poorly defined. METHODS We used clodronate liposomes to deplete macrophages in a mouse model of neonatal hyperoxia-induced lung injury to evaluate if EPC loss in BPD lungs could be an effect of macrophage infiltration. We further generated in vitro culture systems initiated with cord blood (CB)-derived CD34+ EPCs and neonatal macrophages either polarized from CB-derived monocytes or isolated from tracheal aspirates of human preterm infants requiring mechanical ventilation and oxygen supplementation, to identify EV-transmitted molecular mechanism that is critical for inhibitory actions of hyperoxic macrophages on EPCs. RESULTS Initial experiments using mouse model identified the crucial role of macrophage infiltration in eliciting significant reduction of c-Kit+ EPCs in BPD lungs. Further examination of this concept in human system, we found that hyperoxia-exposed neonatal macrophages hamper human CD34+ EPC maintenance and impair endothelial function in the differentiated progeny via the EV transmission of miR-23a-3p. Notably, treatment with antagomiR-23a-3p to silence miR-23a-3p in vivo enhances c-Kit+ EPC maintenance, and increases capillary density, and consequently mitigates simplified alveolarization in BPD lungs. CONCLUSION Our findings highlight the importance of pulmonary intercellular communication in the pathophysiology of BPD, by identifying a linkage through vesicle transfer of miR-23a-3p from hyperoxic macrophages to EPCs, and thus demonstrating potential for novel therapeutic target in BPD.
Collapse
Affiliation(s)
- Xuan Wang
- Laboratory of Neonatology, Department of Neonatology, Shenzhen Maternity and Child Healthcare Hospital, Shenzhen, 518000, China
| | - Fang Yao
- Laboratory of Neonatology, Department of Neonatology, Shenzhen Maternity and Child Healthcare Hospital, Shenzhen, 518000, China
| | - Lingling Yang
- Laboratory of Neonatology, Department of Neonatology, Shenzhen Maternity and Child Healthcare Hospital, Shenzhen, 518000, China
| | - Dongshan Han
- Laboratory of Neonatology, Department of Neonatology, Shenzhen Maternity and Child Healthcare Hospital, Shenzhen, 518000, China
| | - Yali Zeng
- Laboratory of Neonatology, Department of Neonatology, Shenzhen Maternity and Child Healthcare Hospital, Shenzhen, 518000, China
- The First Clinical Medical School, Southern Medical University, Guangzhou, China
| | - Zilu Huang
- Laboratory of Neonatology, Department of Neonatology, Shenzhen Maternity and Child Healthcare Hospital, Shenzhen, 518000, China
| | - Chuanzhong Yang
- Laboratory of Neonatology, Department of Neonatology, Shenzhen Maternity and Child Healthcare Hospital, Shenzhen, 518000, China
- The First Clinical Medical School, Southern Medical University, Guangzhou, China
- Shenzhen Key Laboratory of Maternal and Child Health and Diseases, Shenzhen, China
| | - Bingchun Lin
- Laboratory of Neonatology, Department of Neonatology, Shenzhen Maternity and Child Healthcare Hospital, Shenzhen, 518000, China.
| | - Xueyu Chen
- Laboratory of Neonatology, Department of Neonatology, Shenzhen Maternity and Child Healthcare Hospital, Shenzhen, 518000, China.
- The First Clinical Medical School, Southern Medical University, Guangzhou, China.
- Shenzhen Key Laboratory of Maternal and Child Health and Diseases, Shenzhen, China.
| |
Collapse
|
|
6
|
Ugale A, Shunmugam D, Pimpale LG, Rebhan E, Baccarini M. Signaling proteins in HSC fate determination are unequally segregated during asymmetric cell division. J Cell Biol 2024; 223:e202310137. [PMID: 38874393 PMCID: PMC11178505 DOI: 10.1083/jcb.202310137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 03/21/2024] [Accepted: 05/13/2024] [Indexed: 06/15/2024] Open
Abstract
Hematopoietic stem cells (HSCs) continuously replenish mature blood cells with limited lifespans. To maintain the HSC compartment while ensuring output of differentiated cells, HSCs undergo asymmetric cell division (ACD), generating two daughter cells with different fates: one will proliferate and give rise to the differentiated cells' progeny, and one will return to quiescence to maintain the HSC compartment. A balance between MEK/ERK and mTORC1 pathways is needed to ensure HSC homeostasis. Here, we show that activation of these pathways is spatially segregated in premitotic HSCs and unequally inherited during ACD. A combination of genetic and chemical perturbations shows that an ERK-dependent mechanism determines the balance between pathways affecting polarity, proliferation, and metabolism, and thus determines the frequency of asymmetrically dividing HSCs. Our data identify druggable targets that modulate HSC fate determination at the level of asymmetric division.
Collapse
Affiliation(s)
- Amol Ugale
- Department of Microbiology, Max Perutz Labs Vienna, University of Vienna, Immunobiology and Genetics, Vienna, Austria
| | - Dhanlakshmi Shunmugam
- Department of Microbiology, Max Perutz Labs Vienna, University of Vienna, Immunobiology and Genetics, Vienna, Austria
- Vienna BioCenter PhD Program, Doctoral School of the University of Vienna and Medical University of Vienna , Vienna, Austria
| | | | - Elisabeth Rebhan
- Department of Microbiology, Max Perutz Labs Vienna, University of Vienna, Immunobiology and Genetics, Vienna, Austria
| | - Manuela Baccarini
- Department of Microbiology, Max Perutz Labs Vienna, University of Vienna, Immunobiology and Genetics, Vienna, Austria
| |
Collapse
|
|
7
|
Wang J, Zhang Y, Li L, Wang L, Sun S, Wang B, Ge Y, Zhang Z. Nudt15-mediated inflammatory signaling contributes to divergent outcomes in leukemogenesis and hematopoiesis. Leukemia 2024; 38:1958-1970. [PMID: 39025986 DOI: 10.1038/s41375-024-02352-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 07/03/2024] [Accepted: 07/10/2024] [Indexed: 07/20/2024]
Abstract
NUDT15 encodes nucleotide triphosphate diphosphatase that is responsible for metabolizing purine analog drugs, and its genetic mutation results in severe side effects from thiopurine therapy. However, the functions of Nudt15 in leukemic stem cells (LSCs) and hematopoietic stem cells (HSCs) remain unknown. Here we reveal the Nudt15-regulating self-renewal of both mouse LSCs and HSCs. Our data show that Nudt15 negatively regulates murine leukemogenesis and its deficiency prolongs the survival of murine AML recipients by impairing LSC self-renewal, while Nudt15 ablation markedly enhances mouse HSC regenerative potential and self-renewal. Mechanistically, Nudt15 modulates inflammatory signaling in mouse LSCs and HSCs, leading to divergent self-renewal outcomes. Nudt15 depletion inhibits mouse LSC self-renewal by downregulating Ifi30, resulting in elevating intracellular ROS level. Gata2, a key regulator, is required for Nudt15-mediating inflammatory signaling in mouse HSCs. Collectively, our results present new crucial roles of Nudt15 in maintaining the functions of mouse LSC and HSC through inflammatory signaling and have a new insight into clinical implications.
Collapse
Affiliation(s)
- Jiachen Wang
- School of Life Sciences, Shanghai University, Shanghai, 200444, China
| | - Yu Zhang
- School of Life Sciences, Shanghai University, Shanghai, 200444, China
| | - Lei Li
- Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Liujiao Wang
- School of Life Sciences, Shanghai University, Shanghai, 200444, China
| | - Shuainan Sun
- Qianweichang College, Shanghai University, Shanghai, 200444, China
| | - Bowu Wang
- School of Life Sciences, Shanghai University, Shanghai, 200444, China
| | - Yanwen Ge
- School of Life Sciences, Shanghai University, Shanghai, 200444, China
| | - Zhonghui Zhang
- School of Life Sciences, Shanghai University, Shanghai, 200444, China.
- Shaoxing Institute of Technology, Shanghai University, Shaoxing, 312000, China.
| |
Collapse
|
|
8
|
Chang VY, He Y, Grohe S, Brady MR, Chan A, Kadam RS, Fang T, Pang A, Pohl K, Tran E, Li M, Kan J, Zhang Y, Lu JJ, Sasine JP, Himburg HA, Yue P, Chute JP. Epidermal growth factor augments the self-renewal capacity of aged hematopoietic stem cells. iScience 2024; 27:110306. [PMID: 39055915 PMCID: PMC11269946 DOI: 10.1016/j.isci.2024.110306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 02/19/2024] [Accepted: 06/17/2024] [Indexed: 07/28/2024] Open
Abstract
Hematopoietic aging is associated with decreased hematopoietic stem cell (HSC) self-renewal capacity and myeloid skewing. We report that culture of bone marrow (BM) HSCs from aged mice with epidermal growth factor (EGF) suppressed myeloid skewing, increased multipotent colony formation, and increased HSC repopulation in primary and secondary transplantation assays. Mice transplanted with aged, EGF-treated HSCs displayed increased donor cell engraftment within BM HSCs and systemic administration of EGF to aged mice increased HSC self-renewal capacity in primary and secondary transplantation assays. Expression of a dominant negative EGFR in Scl/Tal1+ hematopoietic cells caused increased myeloid skewing and depletion of long term-HSCs in 15-month-old mice. EGF treatment decreased DNA damage in aged HSCs and shifted the transcriptome of aged HSCs from genes regulating cell death to genes involved in HSC self-renewal and DNA repair but had no effect on HSC senescence. These data suggest that EGFR signaling regulates the repopulating capacity of aged HSCs.
Collapse
Affiliation(s)
- Vivian Y. Chang
- Division of Hematology-Oncology, Department of Pediatrics, UCLA, Los Angeles, CA, USA
- Children’s Discovery and Innovation Institute, UCLA, Los Angeles, CA, USA
- Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA
| | - Yuwei He
- Division of Hematology & Cellular Therapy, Cedars Sinai Medical Center, Los Angeles, CA, USA
| | - Samantha Grohe
- Division of Hematology & Cellular Therapy, Cedars Sinai Medical Center, Los Angeles, CA, USA
| | - Morgan R. Brady
- Division of Hematology & Cellular Therapy, Cedars Sinai Medical Center, Los Angeles, CA, USA
| | - Aldi Chan
- Division of Hematology & Cellular Therapy, Cedars Sinai Medical Center, Los Angeles, CA, USA
| | - Rucha S. Kadam
- Division of Hematology & Cellular Therapy, Cedars Sinai Medical Center, Los Angeles, CA, USA
| | - Tiancheng Fang
- Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA
| | - Amara Pang
- Division of Hematology/Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Katherine Pohl
- Division of Hematology/Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Evelyn Tran
- Division of Hematology/Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Michelle Li
- Division of Hematology/Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Jenny Kan
- Division of Hematology/Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Yurun Zhang
- Molecular Biology Institute, UCLA, Los Angeles, CA 90095, USA
| | - Josie J. Lu
- Applied Genomics, Computation and Translational Core, Cedars Sinai Medical Center, Los Angeles, CA, USA
| | - Joshua P. Sasine
- Division of Hematology & Cellular Therapy, Cedars Sinai Medical Center, Los Angeles, CA, USA
| | - Heather A. Himburg
- Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Peibin Yue
- Division of Hematology & Cellular Therapy, Cedars Sinai Medical Center, Los Angeles, CA, USA
| | - John P. Chute
- Division of Hematology & Cellular Therapy, Cedars Sinai Medical Center, Los Angeles, CA, USA
- Board of Governors Regenerative Medicine Institute, Cedars Sinai Medical Center, Los Angeles, CA 90095, USA
- Samuel Oschin Cancer Center, Cedars Sinai Medical Center, Los Angeles, CA 90095, USA
- Department of Medicine, Cedars Sinai Medical Center, Los Angeles, CA 91361, USA
| |
Collapse
|
|
9
|
Zhou Q, Li Z, Xi Y. EV-mediated intercellular communication in acute myeloid leukemia: Transport of genetic materials in the bone marrow microenvironment. Exp Hematol 2024; 133:104175. [PMID: 38311165 DOI: 10.1016/j.exphem.2024.104175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 01/13/2024] [Accepted: 01/17/2024] [Indexed: 02/10/2024]
Abstract
Acute myeloid leukemia (AML) is a common hematological cancer. Cancer cells exchange information with the surrounding microenvironment, which can be transmitted by extracellular vesicles (EVs). In recent years, the genetic materials transported by EVs have attracted attention due to their important roles in different pathological processes. EV-derived ncRNAs (EV-ncRNAs) regulate physiological functions and maintain homeostasis, mainly including microRNAs, long noncoding RNAs, and circular RNAs. However, the mechanism of involvement and potential clinical application of EV-ncRNAs in AML have not been reported. Given the unique importance of the bone marrow microenvironment (BMME) for AML, a greater understanding of the communication between leukemic cells and the BMME is needed to improve the prognosis of patients and reduce the incidence of recurrence. Additionally, studies on leukemic EV-ncRNA transport guide the design of new diagnostic and therapeutic tools for AML. This review systematically describes intercellular communication in the BMME of AML and emphasizes the role of EVs. More importantly, we focus on the information transmission of EV-ncRNAs in the BMME to explore their clinical application as potential biomarkers and therapeutic targets.
Collapse
MESH Headings
- Humans
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/metabolism
- Leukemia, Myeloid, Acute/pathology
- Extracellular Vesicles/metabolism
- Extracellular Vesicles/genetics
- Cell Communication
- Tumor Microenvironment
- Bone Marrow/metabolism
- Bone Marrow/pathology
- Animals
- RNA, Untranslated/genetics
- RNA, Untranslated/metabolism
- RNA, Neoplasm/genetics
- RNA, Neoplasm/metabolism
Collapse
Affiliation(s)
- Qi Zhou
- The First Clinical Medical College of Lanzhou University, Lanzhou, Gansu, China
| | - Zijian Li
- The First Clinical Medical College of Lanzhou University, Lanzhou, Gansu, China; Department of Hematology, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Yaming Xi
- The First Clinical Medical College of Lanzhou University, Lanzhou, Gansu, China; Department of Hematology, The First Hospital of Lanzhou University, Lanzhou, Gansu, China.
| |
Collapse
|
|
10
|
Dangoni GD, Teixeira ACB, da Costa SS, Scliar MO, Carvalho LML, Silva LN, Novak EM, Vince CSC, Maschietto MC, Sugayama SMM, Odone-Filho V, Krepischi ACV. Germline mutations in cancer predisposition genes among pediatric patients with cancer and congenital anomalies. Pediatr Res 2024; 95:1346-1355. [PMID: 38182823 DOI: 10.1038/s41390-023-03000-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 11/08/2023] [Accepted: 12/20/2023] [Indexed: 01/07/2024]
Abstract
BACKGROUND Childhood cancer has a poorly known etiology, and investigating the underlying genetic background may provide novel insights. A recognized association exists between non-chromosomal birth defects and childhood cancer susceptibility. METHODS We performed whole-exome sequencing and chromosomal microarray analysis in a cohort of childhood cancer (22 individuals, 50% with congenital anomalies) to unravel deleterious germline variants. RESULTS A diagnostic yield of 14% was found, encompassing heterozygous variants in bona fide dominant Cancer Predisposition Genes (CPGs). Considering candidate and recessive CPGs harboring monoallelic variants, which were also deemed to play a role in the phenotype, the yield escalated to 45%. Most of the deleterious variants were mapped in genes not conventionally linked to the patient's tumor type. Relevant findings were detected in 55% of the syndromic individuals, mostly variants potentially underlying both phenotypes. CONCLUSION We uncovered a remarkable prevalence of germline deleterious CPG variants, highlighting the significance of a comprehensive genetic analysis in pediatric cancer, especially when coupled with additional clinical signs. Moreover, our findings emphasized the potential for oligogenic inheritance, wherein multiple genes synergistically increase cancer risk. Lastly, our investigation unveiled potentially novel genotype-phenotype associations, such as SETD5 in neuroblastoma, KAT6A in gliomas, JAG1 in hepatoblastomas, and TNFRSF13B in Langerhans cell histiocytosis. IMPACT Novel gene-phenotype associations and candidate genes for pediatric cancer were unraveled, such as KAT6A in gliomas, SETD5 in neuroblastoma, JAG1 in hepatoblastomas, and TNFRSF13B in Langerhans cell histiocytosis. Our analysis revealed a high frequency of deleterious germline variants, particularly in cases accompanied by additional clinical signs, highlighting the importance of a comprehensive genetic evaluation in childhood cancer. Our findings also underscored the potential for oligogenic inheritance in pediatric cancer risk. Understanding the cancer etiology is crucial for genetic counseling, often influencing therapeutic decisions and offering valuable insights into molecular targets for the development of oncological therapies.
Collapse
Affiliation(s)
- Gustavo D Dangoni
- Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, SP, Brazil
| | - Anne Caroline B Teixeira
- Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, SP, Brazil
| | - Silvia S da Costa
- Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, SP, Brazil
| | - Marília O Scliar
- Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, SP, Brazil
| | - Laura M L Carvalho
- Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, SP, Brazil
| | - Luciana N Silva
- Department of Pediatrics, Instituto de Tratamento do Câncer Infantil (ITACI), Faculty of Medicine, University of São Paulo, São Paulo, SP, Brazil
| | - Estela M Novak
- Department of Pediatrics, Instituto de Tratamento do Câncer Infantil (ITACI), Faculty of Medicine, University of São Paulo, São Paulo, SP, Brazil
| | | | | | - Sofia M M Sugayama
- Department of Pediatrics, Instituto de Tratamento do Câncer Infantil (ITACI), Faculty of Medicine, University of São Paulo, São Paulo, SP, Brazil
| | - Vicente Odone-Filho
- Department of Pediatrics, Instituto de Tratamento do Câncer Infantil (ITACI), Faculty of Medicine, University of São Paulo, São Paulo, SP, Brazil
| | - Ana Cristina V Krepischi
- Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, SP, Brazil.
| |
Collapse
|
|
11
|
Chen Z, Guo Q, Huang S, Li L, Wu F, Liu Z, Li Z, Chen T, Song G, Xu S, Chen J, Hou Y. Overcoming adaptive resistance in AML by synergistically targeting FOXO3A-GNG7-mTOR axis with FOXO3A inhibitor Gardenoside and rapamycin. Genes Dis 2024; 11:397-412. [PMID: 37588187 PMCID: PMC10425752 DOI: 10.1016/j.gendis.2023.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 01/02/2023] [Indexed: 01/26/2023] Open
Abstract
Therapeutic targeting FOXO3A (a forkhead transcription factor) represents a promising strategy to suppress acute myeloid leukemia (AML). However, the effective inhibitors that target FOXO3A are lacking and the adaptive response signaling weakens the cytotoxic effect of FOXO3A depletion on AML cells. Here, we show that FOXO3A deficiency induces a compensatory response involved in the reactive activation of mTOR that leads to signaling rebound and adaptive resistance. Mitochondrial metabolism acts downstream of mTOR to provoke activation of JNK/c-JUN via reactive oxygen species (ROS). At the molecular level, FOXO3A directly binds to the promoter of G protein gamma subunit 7 (GNG7) and preserves its expression, while GNG7 interacts with mTOR and restricts phosphorylated activation of mTOR. Consequently, combinatorial inhibition of FOXO3A and mTOR show a synergistic cytotoxic effect on AML cells and prolongs survival in a mouse model of AML. Through a structure-based virtual screening, we report one potent small-molecule FOXO3A inhibitor (Gardenoside) that exhibits a strong effect of anti-FOXO3A DNA binding. Gardenoside synergizes with rapamycin to substantially reduce tumor burden and extend survival in AML patient-derived xenograft model. These results demonstrate that mTOR can mediate adaptive resistance to FOXO3A inhibition and validate a combinatorial approach for treating AML.
Collapse
Affiliation(s)
- Zhe Chen
- Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
- Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, China
| | - Qian Guo
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China
| | - Shichen Huang
- Chongqing Foreign Language School, Chongqing 400039, China
| | - Lei Li
- Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Feng Wu
- Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, China
| | - Zhilong Liu
- Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Zhigang Li
- Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, China
| | - Tao Chen
- Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Guanbin Song
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China
| | - Shuangnian Xu
- Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Jieping Chen
- Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Yu Hou
- Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, China
| |
Collapse
|
|
12
|
Carlock C, Bai Y, Paige-Hood A, Li Q, Nguele Meke F, Zhang ZY. PRL2 inhibition elevates PTEN protein and ameliorates progression of acute myeloid leukemia. JCI Insight 2023; 8:e170065. [PMID: 37665633 PMCID: PMC10619439 DOI: 10.1172/jci.insight.170065] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 08/23/2023] [Indexed: 09/06/2023] Open
Abstract
Overexpression of phosphatases of regenerating liver 2 (PRL2), detected in numerous diverse cancers, is often associated with increased severity and poor patient prognosis. PRL2-catalyzed tyrosine dephosphorylation of the tumor suppressor PTEN results in increased PTEN degradation and has been identified as a mechanism underlying PRL2 oncogenic activity. Overexpression of PRL2, coincident with reduced PTEN protein, is frequently observed in patients with acute myeloid leukemia (AML). In the current study, a PTEN-knockdown AML animal model was generated to assess the effect of conditional PRL2 inhibition on the level of PTEN protein and the development and progression of AML. Inhibition of PRL2 resulted in a significant increase in median animal survival, from 40 weeks to greater than 60 weeks. The prolonged survival reflected delayed expansion of aberrantly differentiated hematopoietic stem cells into leukemia blasts, resulting in extended time required for clinically relevant leukemia blast accumulation in the BM niche. Leukemia blast suppression following PRL2 inhibition was correlated with an increase in PTEN and downregulation of AKT/mTOR-regulated pathways. These observations directly established, in a disease model, the viability of PRL2 inhibition as a therapeutic strategy for improving clinical outcomes in AML and potentially other PTEN-deficient cancers by slowing cancer progression.
Collapse
Affiliation(s)
| | - Yunpeng Bai
- Department of Medicinal Chemistry and Molecular Pharmacology
| | | | - Qinglin Li
- Department of Medicinal Chemistry and Molecular Pharmacology
| | | | - Zhong-Yin Zhang
- Department of Medicinal Chemistry and Molecular Pharmacology
- Department of Chemistry
- Institute for Cancer Research, and
- Institute for Drug Discovery, Purdue University, West Lafayette, Indiana, USA
| |
Collapse
|
|
13
|
Pendse S, Chavan S, Kale V, Vaidya A. A comprehensive analysis of cell-autonomous and non-cell-autonomous regulation of myeloid leukemic cells: The prospect of developing novel niche-targeting therapies. Cell Biol Int 2023; 47:1667-1683. [PMID: 37554060 DOI: 10.1002/cbin.12078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 07/12/2023] [Accepted: 07/21/2023] [Indexed: 08/10/2023]
Abstract
Leukemic cells (LCs) arise from the hematopoietic stem/and progenitor cells (HSCs/HSPCs) and utilize cues from the bone marrow microenvironment (BMM) for their regulation in the same way as their normal HSC counterparts. Mesenchymal stromal cells (MSCs), a vital component of the BMM promote leukemogenesis by creating a protective and immune-tolerant microenvironment that can support the survival of LCs, helping them escape chemotherapy, thereby resulting in the relapse of leukemia. Conversely, MSCs also induce apoptosis in the LCs and inhibit their proliferation by interfering with their self-renewal potential. This review discusses the work done so far on cell-autonomous (intrinsic) and MSCs-mediated non-cell-autonomous (extrinsic) regulation of myeloid leukemia with a special focus on the need to investigate the extrinsic regulation of myeloid leukemia to understand the contrasting role of MSCs in leukemogenesis. These mechanisms could be exploited to formulate novel therapeutic strategies that specifically target the leukemic microenvironment.
Collapse
Affiliation(s)
- Shalmali Pendse
- Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Pune, Maharashtra, India
- Symbiosis Centre for Stem Cell Research, Symbiosis International (Deemed University), Pune, Maharashtra, India
| | - Sayali Chavan
- Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Pune, Maharashtra, India
- Symbiosis Centre for Stem Cell Research, Symbiosis International (Deemed University), Pune, Maharashtra, India
| | - Vaijayanti Kale
- Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Pune, Maharashtra, India
- Symbiosis Centre for Stem Cell Research, Symbiosis International (Deemed University), Pune, Maharashtra, India
| | - Anuradha Vaidya
- Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Pune, Maharashtra, India
- Symbiosis Centre for Stem Cell Research, Symbiosis International (Deemed University), Pune, Maharashtra, India
| |
Collapse
|
|
14
|
Xu Z, He L, Wu Y, Yang L, Li C, Wu H. PTEN regulates hematopoietic lineage plasticity via PU.1-dependent chromatin accessibility. Cell Rep 2023; 42:112967. [PMID: 37561626 DOI: 10.1016/j.celrep.2023.112967] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 06/20/2023] [Accepted: 07/26/2023] [Indexed: 08/12/2023] Open
Abstract
PTEN loss in fetal liver hematopoietic stem cells (HSCs) leads to alterations in myeloid, T-, and B-lineage potentials and T-lineage acute lymphoblastic leukemia (T-ALL) development. To explore the mechanism underlying PTEN-regulated hematopoietic lineage choices, we carry out integrated assay for transposase-accessible chromatin using sequencing (ATAC-seq), single-cell RNA-seq, and in vitro culture analyses using in vivo-isolated mouse pre-leukemic HSCs and progenitors. We find that PTEN loss alters chromatin accessibility of key lineage transcription factor (TF) binding sites at the prepro-B stage, corresponding to increased myeloid and T-lineage potentials and reduced B-lineage potential. Importantly, we find that PU.1 is an essential TF downstream of PTEN and that altering PU.1 levels can reprogram the chromatin accessibility landscape and myeloid, T-, and B-lineage potentials in Ptennull prepro-B cells. Our study discovers prepro-B as the key developmental stage underlying PTEN-regulated hematopoietic lineage choices and suggests a critical role of PU.1 in modulating the epigenetic state and lineage plasticity of prepro-B progenitors.
Collapse
Affiliation(s)
- Zihan Xu
- The MOE Key Laboratory of Cell Proliferation and Differentiation, Center for Bioinformatics, School of Life Sciences, Peking University, Beijing, China; Center for Statistical Science, Peking University, Beijing, China
| | - Libing He
- The MOE Key Laboratory of Cell Proliferation and Differentiation, Center for Bioinformatics, School of Life Sciences, Peking University, Beijing, China; Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
| | - Yilin Wu
- The MOE Key Laboratory of Cell Proliferation and Differentiation, Center for Bioinformatics, School of Life Sciences, Peking University, Beijing, China; Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
| | - Lu Yang
- The MOE Key Laboratory of Cell Proliferation and Differentiation, Center for Bioinformatics, School of Life Sciences, Peking University, Beijing, China; Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
| | - Cheng Li
- The MOE Key Laboratory of Cell Proliferation and Differentiation, Center for Bioinformatics, School of Life Sciences, Peking University, Beijing, China; Center for Statistical Science, Peking University, Beijing, China.
| | - Hong Wu
- The MOE Key Laboratory of Cell Proliferation and Differentiation, Center for Bioinformatics, School of Life Sciences, Peking University, Beijing, China; Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.
| |
Collapse
|
|
15
|
Park MN. The Therapeutic Potential of a Strategy to Prevent Acute Myeloid Leukemia Stem Cell Reprogramming in Older Patients. Int J Mol Sci 2023; 24:12037. [PMID: 37569414 PMCID: PMC10418941 DOI: 10.3390/ijms241512037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 07/22/2023] [Accepted: 07/25/2023] [Indexed: 08/13/2023] Open
Abstract
Acute myeloid leukemia (AML) is the most common and incurable leukemia subtype. Despite extensive research into the disease's intricate molecular mechanisms, effective treatments or expanded diagnostic or prognostic markers for AML have not yet been identified. The morphological, immunophenotypic, cytogenetic, biomolecular, and clinical characteristics of AML patients are extensive and complex. Leukemia stem cells (LSCs) consist of hematopoietic stem cells (HSCs) and cancer cells transformed by a complex, finely-tuned interaction that causes the complexity of AML. Microenvironmental regulation of LSCs dormancy and the diagnostic and therapeutic implications for identifying and targeting LSCs due to their significance in the pathogenesis of AML are discussed in this review. It is essential to perceive the relationship between the niche for LSCs and HSCs, which together cause the progression of AML. Notably, methylation is a well-known epigenetic change that is significant in AML, and our data also reveal that microRNAs are a unique factor for LSCs. Multiple-targeted approaches to reduce the risk of epigenetic factors, such as the administration of natural compounds for the elimination of local LSCs, may prevent potentially fatal relapses. Furthermore, the survival analysis of overlapping genes revealed that specific targets had significant effects on the survival and prognosis of patients. We predict that the multiple-targeted effects of herbal products on epigenetic modification are governed by different mechanisms in AML and could prevent potentially fatal relapses. Thus, these strategies can facilitate the incorporation of herbal medicine and natural compounds into the advanced drug discovery and development processes achievable with Network Pharmacology research.
Collapse
Affiliation(s)
- Moon Nyeo Park
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemungu, Seoul 05253, Republic of Korea
| |
Collapse
|
|
16
|
Dutta S, Shah RB, Singhal S, Dutta SB, Bansal S, Sinha S, Haque M. Metformin: A Review of Potential Mechanism and Therapeutic Utility Beyond Diabetes. Drug Des Devel Ther 2023; 17:1907-1932. [PMID: 37397787 PMCID: PMC10312383 DOI: 10.2147/dddt.s409373] [Citation(s) in RCA: 56] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Accepted: 06/10/2023] [Indexed: 07/04/2023] Open
Abstract
Metformin has been designated as one of the most crucial first-line therapeutic agents in the management of type 2 diabetes mellitus. Primarily being an antihyperglycemic agent, metformin also has a plethora of pleiotropic effects on various systems and processes. It acts majorly by activating AMPK (Adenosine Monophosphate-Activated Protein Kinase) in the cells and reducing glucose output from the liver. It also decreases advanced glycation end products and reactive oxygen species production in the endothelium apart from regulating the glucose and lipid metabolism in the cardiomyocytes, hence minimizing the cardiovascular risks. Its anticancer, antiproliferative and apoptosis-inducing effects on malignant cells might prove instrumental in the malignancy of organs like the breast, kidney, brain, ovary, lung, and endometrium. Preclinical studies have also shown some evidence of metformin's neuroprotective role in Parkinson's disease, Alzheimer's disease, multiple sclerosis and Huntington's disease. Metformin exerts its pleiotropic effects through varied pathways of intracellular signalling and exact mechanism in the majority of them remains yet to be clearly defined. This article has extensively reviewed the therapeutic benefits of metformin and the details of its mechanism for a molecule of boon in various conditions like diabetes, prediabetes, obesity, polycystic ovarian disease, metabolic derangement in HIV, various cancers and aging.
Collapse
Affiliation(s)
- Siddhartha Dutta
- Department of Pharmacology, All India Institute of Medical Sciences, Rajkot, Gujarat, India
| | - Rima B Shah
- Department of Pharmacology, All India Institute of Medical Sciences, Rajkot, Gujarat, India
| | - Shubha Singhal
- Department of Pharmacology, All India Institute of Medical Sciences, Rajkot, Gujarat, India
| | - Sudeshna Banerjee Dutta
- Department of Medical Surgical Nursing, Shri Anand Institute of Nursing, Rajkot, Gujarat, 360005, India
| | - Sumit Bansal
- Department of Anaesthesiology, All India Institute of Medical Sciences, Rajkot, Gujarat, India
| | - Susmita Sinha
- Department of Physiology, Khulna City Medical College and Hospital, Khulna, Bangladesh
| | - Mainul Haque
- Unit of Pharmacology, Faculty of Medicine and Defence Health, Universiti Pertahanan Nasional Malaysia (National Defence University of Malaysia), Kuala Lumpur, 57000, Malaysia
| |
Collapse
|
|
17
|
Folgado-Marco V, Ames K, Chuen J, Gritsman K, Baker NE. Haploinsufficiency of the essential gene Rps12 causes defects in erythropoiesis and hematopoietic stem cell maintenance. eLife 2023; 12:e69322. [PMID: 37272618 PMCID: PMC10287158 DOI: 10.7554/elife.69322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 04/26/2023] [Indexed: 06/06/2023] Open
Abstract
Ribosomal protein (Rp) gene haploinsufficiency can result in Diamond-Blackfan Anemia (DBA), characterized by defective erythropoiesis and skeletal defects. Some mouse Rp mutations recapitulate DBA phenotypes, although others lack erythropoietic or skeletal defects. We generated a conditional knockout mouse to partially delete Rps12. Homozygous Rps12 deletion resulted in embryonic lethality. Mice inheriting the Rps12KO/+ genotype had growth and morphological defects, pancytopenia, and impaired erythropoiesis. A striking reduction in hematopoietic stem cells (HSCs) and progenitors in the bone marrow (BM) was associated with decreased ability to repopulate the blood system after competitive and non-competitive BM transplantation. Rps12KO/+ lost HSC quiescence, experienced ERK and MTOR activation, and increased global translation in HSC and progenitors. Post-natal heterozygous deletion of Rps12 in hematopoietic cells using Tal1-Cre-ERT also resulted in pancytopenia with decreased HSC numbers. However, post-natal Cre-ERT induction led to reduced translation in HSCs and progenitors, suggesting that this is the most direct consequence of Rps12 haploinsufficiency in hematopoietic cells. Thus, RpS12 has a strong requirement in HSC function, in addition to erythropoiesis.
Collapse
Affiliation(s)
| | - Kristina Ames
- Department of Medical Oncology, Albert Einstein College of MedicineBronxUnited States
- Department of Cell Biology, Albert Einstein College of MedicineBronxUnited States
| | - Jacky Chuen
- Department of Genetics, Albert Einstein College of MedicineBronxUnited States
| | - Kira Gritsman
- Department of Medical Oncology, Albert Einstein College of MedicineBronxUnited States
- Department of Cell Biology, Albert Einstein College of MedicineBronxUnited States
| | - Nicholas E Baker
- Department of Genetics, Albert Einstein College of MedicineBronxUnited States
| |
Collapse
|
|
18
|
Mannick JB, Lamming DW. Targeting the biology of aging with mTOR inhibitors. NATURE AGING 2023; 3:642-660. [PMID: 37142830 PMCID: PMC10330278 DOI: 10.1038/s43587-023-00416-y] [Citation(s) in RCA: 139] [Impact Index Per Article: 69.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 04/07/2023] [Indexed: 05/06/2023]
Abstract
Inhibition of the protein kinase mechanistic target of rapamycin (mTOR) with the Food and Drug Administration (FDA)-approved therapeutic rapamycin promotes health and longevity in diverse model organisms. More recently, specific inhibition of mTORC1 to treat aging-related conditions has become the goal of basic and translational scientists, clinicians and biotechnology companies. Here, we review the effects of rapamycin on the longevity and survival of both wild-type mice and mouse models of human diseases. We discuss recent clinical trials that have explored whether existing mTOR inhibitors can safely prevent, delay or treat multiple diseases of aging. Finally, we discuss how new molecules may provide routes to the safer and more selective inhibition of mTOR complex 1 (mTORC1) in the decade ahead. We conclude by discussing what work remains to be done and the questions that will need to be addressed to make mTOR inhibitors part of the standard of care for diseases of aging.
Collapse
Affiliation(s)
| | - Dudley W Lamming
- Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.
| |
Collapse
|
|
19
|
Wang Y, Yu Y, Yang W, Wu L, Yang Y, Lu Q, Zhou J. SETD4 Confers Cancer Stem Cell Chemoresistance in Nonsmall Cell Lung Cancer Patients via the Epigenetic Regulation of Cellular Quiescence. Stem Cells Int 2023; 2023:7367854. [PMID: 37274024 PMCID: PMC10239305 DOI: 10.1155/2023/7367854] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 04/23/2023] [Accepted: 05/08/2023] [Indexed: 06/06/2023] Open
Abstract
Increasing evidence indicates that quiescent cancer stem cells (CSCs) are a root cause of chemoresistance. SET domain-containing protein 4 (SETD4) epigenetically regulates cell quiescence in breast cancer stem cells (BCSCs), and SETD4-positive BCSCs are chemoradioresistant. However, the role of SETD4 in chemoresistance, tumor progression, and prognosis in nonsmall cell lung cancer (NSCLC) patients is unclear. Here, SETD4-positive cells were identified as quiescent lung cancer stem cells (qLCSCs) since they expressed high levels of ALDH1 and CD133 and low levels of Ki67. SETD4 expression was significantly higher in advanced-stage NSCLC tissues than in early-stage NSCLC tissues and significantly higher in samples from the chemoresistant group than in those from the chemosensitive group. Patients with high SETD4 expression had shorter progression-free survival (PFS) times than those with low SETD4 expression. SETD4 facilitated heterochromatin formation via H4K20me3, thereby leading to cell quiescence. RNA-seq analysis showed upregulation of genes involved in cell proliferation, glucose metabolism, and PI3K-AKT signaling in activated qLCSCs (A-qLCSCs) compared with qLCSCs. In addition, SETD4 overexpression facilitated PTEN-mediated inhibition of the PI3K-mTOR pathway. In summary, SETD4 confers chemoresistance, tumor progression, and a poor prognosis by regulating CSCs in NSCLC patients.
Collapse
Affiliation(s)
- Yuehong Wang
- Department of Respiratory Disease, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Yuman Yu
- Department of Geriatrics, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Weijun Yang
- MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou 310058, China
| | - Linying Wu
- Department of Respiratory Disease, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Yaoshun Yang
- MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou 310058, China
| | - Qianyun Lu
- MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou 310058, China
| | - Jianying Zhou
- Department of Respiratory Disease, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| |
Collapse
|
|
20
|
Ling B, Xu Y, Qian S, Xiang Z, Xuan S, Wu J. Regulation of hematopoietic stem cells differentiation, self-renewal, and quiescence through the mTOR signaling pathway. Front Cell Dev Biol 2023; 11:1186850. [PMID: 37228652 PMCID: PMC10203478 DOI: 10.3389/fcell.2023.1186850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 04/28/2023] [Indexed: 05/27/2023] Open
Abstract
Hematopoietic stem cells (HSCs) are important for the hematopoietic system because they can self-renew to increase their number and differentiate into all the blood cells. At a steady state, most of the HSCs remain in quiescence to preserve their capacities and protect themselves from damage and exhaustive stress. However, when there are some emergencies, HSCs are activated to start their self-renewal and differentiation. The mTOR signaling pathway has been shown as an important signaling pathway that can regulate the differentiation, self-renewal, and quiescence of HSCs, and many types of molecules can regulate HSCs' these three potentials by influencing the mTOR signaling pathway. Here we review how mTOR signaling pathway regulates HSCs three potentials, and introduce some molecules that can work as the regulator of HSCs' these potentials through the mTOR signaling. Finally, we outline the clinical significance of studying the regulation of HSCs three potentials through the mTOR signaling pathway and make some predictions.
Collapse
Affiliation(s)
- Bai Ling
- Department of Pharmacy, The Yancheng Clinical College of Xuzhou Medical University, The First People’s Hospital of Yancheng, Yancheng, Jiangsu, China
| | - Yunyang Xu
- Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Siyuan Qian
- The Second School of Clinical Medicine, Wenzhou Medical University, Wenzhou, China
| | - Ze Xiang
- Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Shihai Xuan
- Department of Laboratory Medicine, The People’s Hospital of Dongtai City, Dongtai, China
| | - Jian Wu
- Department of Clinical Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu, China
| |
Collapse
|
|
21
|
Nanba D, Sakabe JI, Mosig J, Brouard M, Toki F, Shimokawa M, Kamiya M, Braschler T, Azzabi F, Droz-Georget Lathion S, Johnsson K, Roy K, Schmid CD, Bureau JB, Rochat A, Barrandon Y. Low temperature and mTOR inhibition favor stem cell maintenance in human keratinocyte cultures. EMBO Rep 2023:e55439. [PMID: 37139607 DOI: 10.15252/embr.202255439] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 03/26/2023] [Accepted: 04/14/2023] [Indexed: 05/05/2023] Open
Abstract
Adult autologous human epidermal stem cells can be extensively expanded ex vivo for cell and gene therapy. Identifying the mechanisms involved in stem cell maintenance and defining culture conditions to maintain stemness is critical, because an inadequate environment can result in the rapid conversion of stem cells into progenitors/transient amplifying cells (clonal conversion), with deleterious consequences on the quality of the transplants and their ability to engraft. Here, we demonstrate that cultured human epidermal stem cells respond to a small drop in temperature through thermoTRP channels via mTOR signaling. Exposure of cells to rapamycin or a small drop in temperature induces the nuclear translocation of mTOR with an impact on gene expression. We also demonstrate by single-cell analysis that long-term inhibition of mTORC1 reduces clonal conversion and favors the maintenance of stemness. Taken together, our results demonstrate that human keratinocyte stem cells can adapt to environmental changes (e.g., small variations in temperature) through mTOR signaling and constant inhibition of mTORC1 favors stem cell maintenance, a finding of high importance for regenerative medicine applications.
Collapse
Affiliation(s)
- Daisuke Nanba
- Laboratory of Stem Cell Dynamics, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
- Department of Experimental Surgery, Lausanne University Hospital, Lausanne, Switzerland
- Division of Aging and Regeneration, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Jun-Ichi Sakabe
- Duke-NUS Medical School, Singapore City, Singapore
- Department of Plastic, Reconstructive and Aesthetic Surgery, Singapore General Hospital and A*STAR Skin Research Labs, Singapore City, Singapore
| | - Johannes Mosig
- Laboratory of Stem Cell Dynamics, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
- Department of Experimental Surgery, Lausanne University Hospital, Lausanne, Switzerland
| | - Michel Brouard
- Laboratory of Stem Cell Dynamics, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
- Department of Experimental Surgery, Lausanne University Hospital, Lausanne, Switzerland
| | - Fujio Toki
- Laboratory of Stem Cell Dynamics, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
- Department of Experimental Surgery, Lausanne University Hospital, Lausanne, Switzerland
- Division of Aging and Regeneration, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Mariko Shimokawa
- Division of Aging and Regeneration, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Mako Kamiya
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
| | - Thomas Braschler
- Laboratory of Stem Cell Dynamics, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
- Department of Experimental Surgery, Lausanne University Hospital, Lausanne, Switzerland
- Institute of Chemical Sciences and Engineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Fahd Azzabi
- Laboratory of Stem Cell Dynamics, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
- Department of Experimental Surgery, Lausanne University Hospital, Lausanne, Switzerland
| | - Stéphanie Droz-Georget Lathion
- Laboratory of Stem Cell Dynamics, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
- Department of Experimental Surgery, Lausanne University Hospital, Lausanne, Switzerland
| | - Kai Johnsson
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
| | - Keya Roy
- Duke-NUS Medical School, Singapore City, Singapore
- Department of Plastic, Reconstructive and Aesthetic Surgery, Singapore General Hospital and A*STAR Skin Research Labs, Singapore City, Singapore
| | - Christoph D Schmid
- Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
| | - Jean-Baptiste Bureau
- Laboratory of Stem Cell Dynamics, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
- Department of Experimental Surgery, Lausanne University Hospital, Lausanne, Switzerland
| | - Ariane Rochat
- Laboratory of Stem Cell Dynamics, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
- Department of Experimental Surgery, Lausanne University Hospital, Lausanne, Switzerland
| | - Yann Barrandon
- Laboratory of Stem Cell Dynamics, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
- Department of Experimental Surgery, Lausanne University Hospital, Lausanne, Switzerland
- Duke-NUS Medical School, Singapore City, Singapore
- Department of Plastic, Reconstructive and Aesthetic Surgery, Singapore General Hospital and A*STAR Skin Research Labs, Singapore City, Singapore
| |
Collapse
|
|
22
|
Sharma P, Kaushal N, Saleth LR, Ghavami S, Dhingra S, Kaur P. Oxidative stress-induced apoptosis and autophagy: Balancing the contrary forces in spermatogenesis. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166742. [PMID: 37146914 DOI: 10.1016/j.bbadis.2023.166742] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 04/18/2023] [Accepted: 04/27/2023] [Indexed: 05/07/2023]
Abstract
Spermatogenesis is a complex process in the testis and is a cornerstone of male infertility. The abundance of unsaturated fatty acid and high cell division rate make male germs cells prone to DNA deterioration. ROS-mediated oxidative stress triggers DNA damage, autophagy, and apoptosis in male germ cells, which are critical causative factors that lead to male infertility. The complex connection and molecular crosstalk between apoptosis and autophagy is seen at multifaceted levels that interconnect the signaling pathways of these two processes. Multilevel interaction between apoptosis and autophagy is a seamless state of survival and death in response to various stressors. Interaction between multiple genes and proteins such as the mTor signaling pathway, Atg12 proteins, and the death adapter proteins, such as Beclin 1, p53, and Bcl-2 family proteins, validates such a link between these two phenomena. Testicular cells being epigenetically different from somatic cells, undergo numerous significant epigenetic transitions, and ROS modulates the epigenetic framework of mature sperm. Epigenetic deregulation of apoptosis and autophagy under oxidative stress conditions can cause sperm cell damage. The current review recapitulates the current role of prevailing stressors that generate oxidative stress leading to the induction of apoptosis and autophagy in the male reproductive system. Considering the pathophysiological consequences of ROS-mediated apoptosis and autophagy, a combinatorial approach, including apoptosis inhibition and autophagy activation, a therapeutic strategy to treat male idiopathic infertility. Understanding the crosslink between apoptosis and autophagy under stress conditions in male germ cells may play an essential role in developing therapeutic strategies to treat infertility.
Collapse
Affiliation(s)
- Parul Sharma
- Department of Biotechnology, Thapar Institute of Engineering & Technology, Patiala, Punjab 147004, India
| | - Naveen Kaushal
- Department of Biophysics, Panjab University, Chandigarh 160014, India
| | - Leena Regi Saleth
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Department of Physiology and Pathophysiology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba R2H 2A6, Canada
| | - Saeid Ghavami
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; Research Institute of Hematology and Oncology, Cancer Care Manitoba, Winnipeg, MB R3E 0V9, Canada; Faculty of Medicine in Zabrze, University of Technology in Katowice, Academia of Silesia, 41-800 Zabrze, Poland
| | - Sanjiv Dhingra
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Department of Physiology and Pathophysiology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba R2H 2A6, Canada
| | - Parminder Kaur
- Department of Biotechnology, University Institute of Engineering & Technology, Panjab University, Chandigarh 160024, India.
| |
Collapse
|
|
23
|
Mendoza-Castrejon J, Magee JA. Layered immunity and layered leukemogenicity: Developmentally restricted mechanisms of pediatric leukemia initiation. Immunol Rev 2023; 315:197-215. [PMID: 36588481 PMCID: PMC10301262 DOI: 10.1111/imr.13180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Hematopoietic stem cells (HSCs) and multipotent progenitor cells (MPPs) arise in successive waves during ontogeny, and their properties change significantly throughout life. Ontological changes in HSCs/MPPs underlie corresponding changes in mechanisms of pediatric leukemia initiation. As HSCs and MPPs progress from fetal to neonatal, juvenile and adult stages of life, they undergo transcriptional and epigenetic reprogramming that modifies immune output to meet age-specific pathogenic challenges. Some immune cells arise exclusively from fetal HSCs/MPPs. We propose that this layered immunity instructs cell fates that underlie a parallel layered leukemogenicity. Indeed, some pediatric leukemias, such as juvenile myelomonocytic leukemia, myeloid leukemia of Down syndrome, and infant pre-B-cell acute lymphoblastic leukemia, are age-restricted. They only present during infancy or early childhood. These leukemias likely arise from fetal progenitors that lose competence for transformation as they age. Other childhood leukemias, such as non-infant pre-B-cell acute lymphoblastic leukemia and acute myeloid leukemia, have mutation profiles that are common in childhood but rare in morphologically similar adult leukemias. These differences could reflect temporal changes in mechanisms of mutagenesis or changes in how progenitors respond to a given mutation at different ages. Interactions between leukemogenic mutations and normal developmental switches offer potential targets for therapy.
Collapse
Affiliation(s)
- Jonny Mendoza-Castrejon
- Department of Pediatrics, Division of Hematology and Oncology, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110
| | - Jeffrey A. Magee
- Department of Pediatrics, Division of Hematology and Oncology, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110
- Department of Genetics, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110
| |
Collapse
|
|
24
|
Han X, Mei Y, Mishra RK, Bi H, Jain AD, Schiltz GE, Zhao B, Sukhanova M, Wang P, Grigorescu AA, Weber PC, Piwinski JJ, Prado MA, Paulo JA, Stephens L, Anderson KE, Abrams CS, Yang J, Ji P. Targeting pleckstrin-2/Akt signaling reduces proliferation in myeloproliferative neoplasm models. J Clin Invest 2023; 133:e159638. [PMID: 36719747 PMCID: PMC10014099 DOI: 10.1172/jci159638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 01/25/2023] [Indexed: 02/01/2023] Open
Abstract
Myeloproliferative neoplasms (MPNs) are characterized by the activated JAK2/STAT pathway. Pleckstrin-2 (Plek2) is a downstream target of the JAK2/STAT5 pathway and is overexpressed in patients with MPNs. We previously revealed that Plek2 plays critical roles in the pathogenesis of JAK2-mutated MPNs. The nonessential roles of Plek2 under physiologic conditions make it an ideal target for MPN therapy. Here, we identified first-in-class Plek2 inhibitors through an in silico high-throughput screening approach and cell-based assays, followed by the synthesis of analogs. Plek2-specific small-molecule inhibitors showed potent inhibitory effects on cell proliferation. Mechanistically, Plek2 interacts with and enhances the activity of Akt through the recruitment of downstream effector proteins. The Plek2-signaling complex also includes Hsp72, which protects Akt from degradation. These functions were blocked by Plek2 inhibitors via their direct binding to the Plek2 dishevelled, Egl-10 and pleckstrin (DEP) domain. The role of Plek2 in activating Akt signaling was further confirmed in vivo using a hematopoietic-specific Pten-knockout mouse model. We next tested Plek2 inhibitors alone or in combination with an Akt inhibitor in various MPN mouse models, which showed significant therapeutic efficacies similar to that seen with the genetic depletion of Plek2. The Plek2 inhibitor was also effective in reducing proliferation of CD34-positive cells from MPN patients. Our studies reveal a Plek2/Akt complex that drives cell proliferation and can be targeted by a class of antiproliferative compounds for MPN therapy.
Collapse
Affiliation(s)
- Xu Han
- Department of Pathology, Feinberg School of Medicine
- Robert H. Lurie Comprehensive Cancer Center
| | - Yang Mei
- Department of Pathology, Feinberg School of Medicine
- Robert H. Lurie Comprehensive Cancer Center
| | - Rama K. Mishra
- Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine
| | - Honghao Bi
- Department of Pathology, Feinberg School of Medicine
- Robert H. Lurie Comprehensive Cancer Center
| | | | - Gary E. Schiltz
- Robert H. Lurie Comprehensive Cancer Center
- Department of Chemistry, and
- Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Baobing Zhao
- Department of Pathology, Feinberg School of Medicine
- Robert H. Lurie Comprehensive Cancer Center
| | - Madina Sukhanova
- Department of Pathology, Feinberg School of Medicine
- Robert H. Lurie Comprehensive Cancer Center
| | - Pan Wang
- Department of Pathology, Feinberg School of Medicine
| | - Arabela A. Grigorescu
- Department of Molecular Biosciences, Weinberg College of Arts & Sciences, Northwestern University, Evanston, Illinois, USA
| | | | | | - Miguel A. Prado
- Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA
| | - Joao A. Paulo
- Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA
| | - Len Stephens
- Signaling Programme, The Babraham Institute, Cambridge, United Kingdom
| | - Karen E. Anderson
- Signaling Programme, The Babraham Institute, Cambridge, United Kingdom
| | - Charles S. Abrams
- Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Jing Yang
- Department of Pathology, Feinberg School of Medicine
- Robert H. Lurie Comprehensive Cancer Center
| | - Peng Ji
- Department of Pathology, Feinberg School of Medicine
- Robert H. Lurie Comprehensive Cancer Center
| |
Collapse
|
|
25
|
Elworthy S, Rutherford HA, Prajsnar TK, Hamilton NM, Vogt K, Renshaw SA, Condliffe AM. Activated PI3K delta syndrome 1 mutations cause neutrophilia in zebrafish larvae. Dis Model Mech 2023; 16:dmm049841. [PMID: 36805642 PMCID: PMC10655814 DOI: 10.1242/dmm.049841] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Accepted: 02/14/2023] [Indexed: 02/22/2023] Open
Abstract
People with activated PI3 kinase delta syndrome 1 (APDS1) suffer from immune deficiency and severe bronchiectasis. APDS1 is caused by dominant activating mutations of the PIK3CD gene that encodes the PI3 kinase delta (PI3Kδ) catalytic subunit. Despite the importance of innate immunity defects in bronchiectasis, there has been limited investigation of neutrophils or macrophages in APDS1 patients or mouse models. Zebrafish embryos provide an ideal system to study neutrophils and macrophages. We used CRISPR-Cas9 and CRISPR-Cpf1, with oligonucleotide-directed homologous repair, to engineer zebrafish equivalents of the two most prevalent human APDS1 disease mutations. These zebrafish pik3cd alleles dominantly caused excessive neutrophilic inflammation in a tail-fin injury model. They also resulted in total body neutrophilia in the absence of any inflammatory stimulus but normal numbers of macrophages. Exposure of zebrafish to the PI3Kδ inhibitor CAL-101 reversed the total body neutrophilia. There was no apparent defect in neutrophil maturation or migration, and tail-fin regeneration was unimpaired. Overall, the finding is of enhanced granulopoeisis, in the absence of notable phenotypic change in neutrophils and macrophages.
Collapse
Affiliation(s)
- Stone Elworthy
- Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield S10 2TN, UK
| | - Holly A. Rutherford
- Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield S10 2TN, UK
| | - Tomasz K. Prajsnar
- Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield S10 2TN, UK
- Department of Evolutionary Immunology, Institute of Zoology and Biomedical Research, Jagiellonian University, Gronostajowa 9, 30-387 Krakow, Poland
| | - Noémie M. Hamilton
- Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield S10 2TN, UK
| | - Katja Vogt
- Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield S10 2TN, UK
| | - Stephen A. Renshaw
- Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield S10 2TN, UK
| | - Alison M. Condliffe
- Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield S10 2TN, UK
| |
Collapse
|
|
26
|
Ames K, Kaur I, Shi Y, Tong MM, Sinclair T, Hemmati S, Glushakow-Smith SG, Tein E, Gurska L, Steidl U, Dubin R, Shan J, Montagna C, Pradhan K, Verma A, Gritsman K. PI3-kinase deletion promotes myelodysplasia by dysregulating autophagy in hematopoietic stem cells. SCIENCE ADVANCES 2023; 9:eade8222. [PMID: 36812307 PMCID: PMC9946350 DOI: 10.1126/sciadv.ade8222] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Accepted: 01/19/2023] [Indexed: 06/18/2023]
Abstract
Myelodysplastic syndrome (MDS) is a clonal malignancy arising in hematopoietic stem cells (HSCs). The mechanisms of MDS initiation in HSCs are still poorly understood. The phosphatidylinositol 3-kinase (PI3K)/AKT pathway is frequently activated in acute myeloid leukemia, but in MDS, PI3K/AKT is often down-regulated. To determine whether PI3K down-regulation can perturb HSC function, we generated a triple knockout (TKO) mouse model with Pik3ca, Pik3cb, and Pik3cd deletion in hematopoietic cells. Unexpectedly, PI3K deficiency caused cytopenias, decreased survival, and multilineage dysplasia with chromosomal abnormalities, consistent with MDS initiation. TKO HSCs exhibit impaired autophagy, and pharmacologic autophagy induction improved HSC differentiation. Using intracellular LC3 and P62 flow cytometry and transmission electron microscopy, we also observed abnormal autophagic degradation in patient MDS HSCs. Therefore, we have uncovered an important protective role for PI3K in maintaining autophagic flux in HSCs to preserve the balance between self-renewal and differentiation and to prevent MDS initiation.
Collapse
Affiliation(s)
- Kristina Ames
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Imit Kaur
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Yang Shi
- Department of Pathology, Montefiore Hospital, Bronx, NY, USA
| | - Meng M. Tong
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Taneisha Sinclair
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Shayda Hemmati
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Shira G. Glushakow-Smith
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Ellen Tein
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Lindsay Gurska
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Ulrich Steidl
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Robert Dubin
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Jidong Shan
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Cristina Montagna
- Department of Radiation Oncology and Genomic Instability and Cancer Genetics, Rutgers Cancer Institute of New Jersey, NJ, USA
| | - Kith Pradhan
- Department of Medical Oncology, Montefiore Hospital, Bronx, NY, USA
| | - Amit Verma
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
- Department of Medical Oncology, Montefiore Hospital, Bronx, NY, USA
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Kira Gritsman
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA
- Department of Medical Oncology, Montefiore Hospital, Bronx, NY, USA
| |
Collapse
|
|
27
|
Zeng X, Wang YP, Man CH. Metabolism in Hematopoiesis and Its Malignancy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1442:45-64. [PMID: 38228958 DOI: 10.1007/978-981-99-7471-9_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/18/2024]
Abstract
Hematopoietic stem cells (HSCs) are multipotent stem cells that can self-renew and generate all blood cells of different lineages. The system is under tight control in order to maintain a precise equilibrium of the HSC pool and the effective production of mature blood cells to support various biological activities. Cell metabolism can regulate different molecular activities, such as epigenetic modification and cell cycle regulation, and subsequently affects the function and maintenance of HSC. Upon malignant transformation, oncogenic drivers in malignant hematopoietic cells can remodel the metabolic pathways for supporting the oncogenic growth. The dysregulation of metabolism results in oncogene addiction, implying the development of malignancy-specific metabolism-targeted therapy. In this chapter, we will discuss the significance of different metabolic pathways in hematopoiesis, specifically, the distinctive metabolic dependency in hematopoietic malignancies and potential metabolic therapy.
Collapse
Affiliation(s)
- Xiaoyuan Zeng
- Division of Haematology, Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Yi-Ping Wang
- Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Cheuk-Him Man
- Division of Haematology, Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
| |
Collapse
|
|
28
|
Skelding KA, Barry DL, Theron DZ, Lincz LF. Bone Marrow Microenvironment as a Source of New Drug Targets for the Treatment of Acute Myeloid Leukaemia. Int J Mol Sci 2022; 24:563. [PMID: 36614005 PMCID: PMC9820412 DOI: 10.3390/ijms24010563] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 12/05/2022] [Accepted: 12/22/2022] [Indexed: 12/30/2022] Open
Abstract
Acute myeloid leukaemia (AML) is a heterogeneous disease with one of the worst survival rates of all cancers. The bone marrow microenvironment is increasingly being recognised as an important mediator of AML chemoresistance and relapse, supporting leukaemia stem cell survival through interactions among stromal, haematopoietic progenitor and leukaemic cells. Traditional therapies targeting leukaemic cells have failed to improve long term survival rates, and as such, the bone marrow niche has become a promising new source of potential therapeutic targets, particularly for relapsed and refractory AML. This review briefly discusses the role of the bone marrow microenvironment in AML development and progression, and as a source of novel therapeutic targets for AML. The main focus of this review is on drugs that modulate/target this bone marrow microenvironment and have been examined in in vivo models or clinically.
Collapse
Affiliation(s)
- Kathryn A. Skelding
- Cancer Cell Biology Research Group, School of Biomedical Sciences and Pharmacy, College of Health Medicine and Wellbeing, The University of Newcastle, Callaghan, NSW 2308, Australia
- Precision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
| | - Daniel L. Barry
- Cancer Cell Biology Research Group, School of Biomedical Sciences and Pharmacy, College of Health Medicine and Wellbeing, The University of Newcastle, Callaghan, NSW 2308, Australia
- Precision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
| | - Danielle Z. Theron
- Cancer Cell Biology Research Group, School of Biomedical Sciences and Pharmacy, College of Health Medicine and Wellbeing, The University of Newcastle, Callaghan, NSW 2308, Australia
- Precision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
| | - Lisa F. Lincz
- Precision Medicine Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
- Hunter Hematology Research Group, Calvary Mater Newcastle Hospital, Waratah, NSW 2298, Australia
| |
Collapse
|
|
29
|
Forester CM, Oses-Prieto JA, Phillips NJ, Miglani S, Pang X, Byeon GW, DeMarco R, Burlingame A, Barna M, Ruggero D. Regulation of eIF4E guides a unique translational program to control erythroid maturation. SCIENCE ADVANCES 2022; 8:eadd3942. [PMID: 36563140 PMCID: PMC9788769 DOI: 10.1126/sciadv.add3942] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 11/22/2022] [Indexed: 05/22/2023]
Abstract
Translation control is essential in balancing hematopoietic precursors and differentiation; however, the mechanisms underlying this program are poorly understood. We found that the activity of the major cap-binding protein eIF4E is unexpectedly regulated in a dynamic manner throughout erythropoiesis that is uncoupled from global protein synthesis rates. Moreover, eIF4E activity directs erythroid maturation, and increased eIF4E expression maintains cells in an early erythroid state associated with a translation program driving the expression of PTPN6 and Igf2bp1. A cytosine-enriched motif in the 5' untranslated region is important for eIF4E-mediated translation specificity. Therefore, selective translation of key target genes necessary for the maintenance of early erythroid states by eIF4E highlights a unique mechanism used by hematopoietic precursors to rapidly elicit erythropoietic maturation upon need.
Collapse
Affiliation(s)
- Craig M. Forester
- Department of Pediatrics, University of Colorado, Denver, CO 80045, USA
- Division of Pediatric Hematology/Oncology/Bone Marrow Transplant, Children’s Hospital Colorado, University of Colorado-Anschutz Medical Campus, Aurora, CO 80045, USA
- Department of Urology, University of California, San Francisco, San Francisco, CA, USA
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA 94158, USA
| | - Juan A. Oses-Prieto
- Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA
| | - Nancy J. Phillips
- Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA
| | - Sohit Miglani
- Department of Urology, University of California, San Francisco, San Francisco, CA, USA
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA 94158, USA
- Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA
- Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA
| | - Xiaming Pang
- Department of Urology, University of California, San Francisco, San Francisco, CA, USA
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA 94158, USA
- Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA
| | - Gun Woo Byeon
- Department of Genetics, Stanford University School of Medicine, Stanford, CA 94309, USA
| | - Rachel DeMarco
- Department of Pediatrics, University of Colorado, Denver, CO 80045, USA
| | - Al Burlingame
- Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA
| | - Maria Barna
- Department of Genetics, Stanford University School of Medicine, Stanford, CA 94309, USA
| | - Davide Ruggero
- Department of Urology, University of California, San Francisco, San Francisco, CA, USA
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA 94158, USA
- Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA
| |
Collapse
|
|
30
|
Zhang Y, Yin YL, Jin ZY, Hu QP, Wu XG. Electroacupuncture Activates Neuroplasticity in the Motor Cortex and Corticospinal Tract via the mTOR Pathway in a Rat P-MCAO Model. BIOMED RESEARCH INTERNATIONAL 2022; 2022:3470685. [PMID: 36440366 PMCID: PMC9683956 DOI: 10.1155/2022/3470685] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 11/03/2022] [Accepted: 11/05/2022] [Indexed: 10/14/2023]
Abstract
Electroacupuncture (EA) combines traditional Chinese medicine acupuncture theory with modern scientific technology. It is a promising therapy for the treatment of cerebrovascular diseases such as cerebral infarction. A large number of clinical studies have shown that EA promotes recovery of neurological function after cerebral infarction, however, the underlying mechanisms behind its effects remain unclear. We tested whether EA stimulation of the Zusanli (ST36) and Neiguan (PC6) acupoints activates neuroplasticity in rats with ischemic stroke and whether this involves the regulation of axonal regeneration through the mTOR pathway. 24 h after permanent middle cerebral artery occlusion (p-MCAO) in rats, EA treatment was started for 20 min, daily, for 14 days. We found that EA significantly reduced Modified Neurological Severity Scores (mNSS), cerebral infarct volume, and apoptosis of neuronal cells. EA also significantly increased the expression of the neuroplasticity-associated proteins GAP-43 and SYN and upregulated the phosphorylation levels of AKT, mTOR, S6, and PTEN to promote CST axon sprouting in the spinal cord at C1-C4 levels. The positive effects of EA were blocked by the administration of the mTOR inhibitor Rapamycin. In short, we found that EA of the Zusanli (ST36) and Neiguan (PC6) acupoints in p-MCAO rats induced neuroprotective and neuroplastic effects by regulating the mTOR signaling pathway. It promoted neuroplasticity activated by axon regeneration in the contralateral cortex and corticospinal tract. Activation of such endogenous remodeling is conducive to neurological recovery and may help explain the positive clinical effects seen in patients with infarcts.
Collapse
Affiliation(s)
- You Zhang
- Department of Traditional Chinese Medicine, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, China
| | - Ya-Long Yin
- Department of Traditional Chinese Medicine, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, China
| | - Zi-Yan Jin
- Department of Traditional Chinese Medicine, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, China
| | - Qi-Ping Hu
- Department of Cell Biology and Genetics, School of Pre-Clinical Medicine, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, China
| | - Xin-gui Wu
- Department of Traditional Chinese Medicine, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, China
| |
Collapse
|
|
31
|
Cell-intrinsic factors governing quiescence vis-à-vis activation of adult hematopoietic stem cells. Mol Cell Biochem 2022; 478:1361-1382. [PMID: 36309884 DOI: 10.1007/s11010-022-04594-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 10/13/2022] [Indexed: 10/31/2022]
Abstract
Hematopoiesis is a highly complex process, regulated by both intrinsic and extrinsic factors. Often, these two regulatory arms work in tandem to maintain the steady-state condition of hematopoiesis. However, at times, certain intrinsic attributes of hematopoietic stem cells (HSCs) override the external stimuli and dominate the outcome. These could be genetic events like mutations or environmentally induced epigenetic or transcriptomic changes. Since leukemic stem cells (LSCs) share molecular pathways that also regulate normal HSCs, identifying specific, dominantly acting intrinsic factors could help in the development of novel therapeutic approaches. Here we have reviewed such dominantly acting intrinsic factors governing quiescence vis-à-vis activation of the HSCs in the face of external forces acting on them. For brevity, we have restricted our review to the articles dealing with adult HSCs of human and mouse origin that have been published in the last 10 years. Hematopoietic stem cells (HSCs) are closely associated with various stromal cells in their microenvironment and, thus, constantly receive signaling cues from them. The illustration depicts some dominantly acting intrinsic or cell-autonomous factors operative in the HSCs. These fall into various categories, such as epigenetic regulators, transcription factors, cell cycle regulators, tumor suppressor genes, signaling pathways, and metabolic regulators, which counteract the outcome of extrinsic signaling exerted by the HSC niche.
Collapse
|
|
32
|
Yin N, Jin G, Ma Y, Zhao H, Zhang G, Li MO, Peng M. SZT2 maintains hematopoietic stem cell homeostasis via nutrient-mediated mTORC1 regulation. J Clin Invest 2022; 132:146272. [PMID: 36250465 PMCID: PMC9566891 DOI: 10.1172/jci146272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Accepted: 08/19/2022] [Indexed: 11/17/2022] Open
Abstract
The mTORC1 pathway coordinates nutrient and growth factor signals to maintain organismal homeostasis. Whether nutrient signaling to mTORC1 regulates stem cell function remains unknown. Here, we show that SZT2 — a protein required for mTORC1 downregulation upon nutrient deprivation — is critical for hematopoietic stem cell (HSC) homeostasis. Ablation of SZT2 in HSCs decreased the reserve and impaired the repopulating capacity of HSCs. Furthermore, ablation of both SZT2 and TSC1 — 2 repressors of mTORC1 on the nutrient and growth factor arms, respectively — led to rapid HSC depletion, pancytopenia, and premature death of the mice. Mechanistically, loss of either SZT2 or TSC1 in HSCs led to only mild elevation of mTORC1 activity and reactive oxygen species (ROS) production. Loss of both SZT2 and TSC1, on the other hand, simultaneously produced a dramatic synergistic effect, with an approximately 10-fold increase of mTORC1 activity and approximately 100-fold increase of ROS production, which rapidly depleted HSCs. These data demonstrate a critical role of nutrient mTORC1 signaling in HSC homeostasis and uncover a strong synergistic effect between nutrient- and growth factor–mediated mTORC1 regulation in stem cells.
Collapse
Affiliation(s)
- Na Yin
- Department of Basic Medical Sciences, School of Medicine, and
- Institute for Immunology, Tsinghua University, Beijing, China
| | - Gang Jin
- Department of Basic Medical Sciences, School of Medicine, and
- Institute for Immunology, Tsinghua University, Beijing, China
| | - Yuying Ma
- Department of Basic Medical Sciences, School of Medicine, and
- Institute for Immunology, Tsinghua University, Beijing, China
| | - Hanfei Zhao
- Department of Basic Medical Sciences, School of Medicine, and
- Institute for Immunology, Tsinghua University, Beijing, China
| | - Guangyue Zhang
- Department of Basic Medical Sciences, School of Medicine, and
- Institute for Immunology, Tsinghua University, Beijing, China
- Tsinghua-Peking Center for Life Sciences, Beijing, China
| | - Ming O. Li
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, New York, USA
| | - Min Peng
- Department of Basic Medical Sciences, School of Medicine, and
- Institute for Immunology, Tsinghua University, Beijing, China
- Tsinghua-Peking Center for Life Sciences, Beijing, China
- Beijing Key Laboratory for Immunological Research on Chronic Diseases, Tsinghua University, Beijing, China
| |
Collapse
|
|
33
|
Chen Y, Li J, Xu L, Găman MA, Zou Z. The genesis and evolution of acute myeloid leukemia stem cells in the microenvironment: From biology to therapeutic targeting. Cell Death Discov 2022; 8:397. [PMID: 36163119 PMCID: PMC9513079 DOI: 10.1038/s41420-022-01193-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 09/12/2022] [Accepted: 09/16/2022] [Indexed: 11/09/2022] Open
Abstract
Acute myeloid leukemia (AML) is a hematological malignancy characterized by cytogenetic and genomic alterations. Up to now, combination chemotherapy remains the standard treatment for leukemia. However, many individuals diagnosed with AML develop chemotherapeutic resistance and relapse. Recently, it has been pointed out that leukemic stem cells (LSCs) are the fundamental cause of drug resistance and AML relapse. LSCs only account for a small subpopulation of all leukemic cells, but possess stem cell properties, including a self-renewal capacity and a multi-directional differentiation potential. LSCs reside in a mostly quiescent state and are insensitive to chemotherapeutic agents. When LSCs reside in a bone marrow microenvironment (BMM) favorable to their survival, they engage into a steady, continuous clonal evolution to better adapt to the action of chemotherapy. Most chemotherapeutic drugs can only eliminate LSC-derived clones, reducing the number of leukemic cells in the BM to a normal range in order to achieve complete remission (CR). LSCs hidden in the BM niche can hardly be targeted or eradicated, leading to drug resistance and AML relapse. Understanding the relationship between LSCs, the BMM, and the generation and evolution laws of LSCs can facilitate the development of effective therapeutic targets and increase the efficiency of LSCs elimination in AML.
Collapse
Affiliation(s)
- Yongfeng Chen
- Department of Basic Medical Sciences, Medical College of Taizhou University, Taizhou, Zhejiang, 318000, China.
| | - Jing Li
- Department of Histology and Embryology, North Sichuan Medical College, Nanchong, Sichuan, 637000, China
| | - Linglong Xu
- Department of Hematology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, 318000, China
| | - Mihnea-Alexandru Găman
- Faculty of Medicine, "Carol Davila" University of Medicine and Pharmacy, 050474, Bucharest, Romania.
- Department of Hematology, Centre of Hematology and Bone Marrow Transplantation, Fundeni Clinical Institute, Bucharest, Romania.
| | - Zhenyou Zou
- Brain Hospital of Guangxi Zhuang Autonomous Region, Liuzhou, Guangxi, 545005, China.
| |
Collapse
|
|
34
|
Fujino T, Asada S, Goyama S, Kitamura T. Mechanisms involved in hematopoietic stem cell aging. Cell Mol Life Sci 2022; 79:473. [PMID: 35941268 PMCID: PMC11072869 DOI: 10.1007/s00018-022-04356-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 04/27/2022] [Accepted: 05/05/2022] [Indexed: 11/03/2022]
Abstract
Hematopoietic stem cells (HSCs) undergo progressive functional decline over time due to both internal and external stressors, leading to aging of the hematopoietic system. A comprehensive understanding of the molecular mechanisms underlying HSC aging will be valuable in developing novel therapies for HSC rejuvenation and to prevent the onset of several age-associated diseases and hematological malignancies. This review considers the general causes of HSC aging that range from cell-intrinsic factors to cell-extrinsic factors. In particular, epigenetics and inflammation have been implicated in the linkage of HSC aging, clonality, and oncogenesis. The challenges in clarifying mechanisms of HSC aging have accelerated the development of therapeutic interventions to rejuvenate HSCs, the major goal of aging research; these details are also discussed in this review.
Collapse
Affiliation(s)
- Takeshi Fujino
- Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan
| | - Shuhei Asada
- The Institute of Laboratory Animals, Tokyo Women's Medical University, Tokyo, 1628666, Japan
| | - Susumu Goyama
- Division of Molecular Oncology Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, 1088639, Japan
| | - Toshio Kitamura
- Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan.
| |
Collapse
|
|
35
|
Kharrat B, Csordás G, Honti V. Peeling Back the Layers of Lymph Gland Structure and Regulation. Int J Mol Sci 2022; 23:7767. [PMID: 35887113 PMCID: PMC9319083 DOI: 10.3390/ijms23147767] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 07/07/2022] [Accepted: 07/11/2022] [Indexed: 12/18/2022] Open
Abstract
During the past 60 years, the fruit fly, Drosophila melanogaster, has proven to be an excellent model to study the regulation of hematopoiesis. This is not only due to the evolutionarily conserved signalling pathways and transcription factors contributing to blood cell fate, but also to convergent evolution that led to functional similarities in distinct species. An example of convergence is the compartmentalization of blood cells, which ensures the quiescence of hematopoietic stem cells and allows for the rapid reaction of the immune system upon challenges. The lymph gland, a widely studied hematopoietic organ of the Drosophila larva, represents a microenvironment with similar features and functions to classical hematopoietic stem cell niches of vertebrates. Lymph gland studies were effectively supported by the unparalleled toolkit developed in Drosophila, which enabled the high-resolution investigation of the cellular composition and regulatory interaction networks of the lymph gland. In this review, we summarize how our understanding of lymph gland structure and hematopoietic cell-to-cell communication evolved during the past decades and compare their analogous features to those of the vertebrate hematopoietic stem cell niche.
Collapse
Affiliation(s)
- Bayan Kharrat
- Drosophila Blood Cell Differentiation Group, Institute of Genetics, Biological Research Centre, P.O. Box 521, H-6701 Szeged, Hungary;
- Faculty of Science and Informatics, Doctoral School of Biology, University of Szeged, P.O. Box 427, H-6720 Szeged, Hungary
| | - Gábor Csordás
- Lysosomal Degradation Research Group, Institute of Genetics, Biological Research Centre, P.O. Box 521, H-6701 Szeged, Hungary;
| | - Viktor Honti
- Drosophila Blood Cell Differentiation Group, Institute of Genetics, Biological Research Centre, P.O. Box 521, H-6701 Szeged, Hungary;
| |
Collapse
|
|
36
|
Bhattacharjee R, Ghosh S, Nath A, Basu A, Biswas O, Patil CR, Kundu CN. Theragnostic strategies harnessing the self-renewal pathways of stem-like cells in the acute myeloid leukemia. Crit Rev Oncol Hematol 2022; 177:103753. [PMID: 35803452 DOI: 10.1016/j.critrevonc.2022.103753] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Revised: 06/21/2022] [Accepted: 07/02/2022] [Indexed: 02/07/2023] Open
Abstract
Acute myelogenous leukemia (AML) is a genetically heterogeneous and aggressive cancer of the Hematopoietic Stem/progenitor cells. It is distinguished by the uncontrollable clonal growth of malignant myeloid stem cells in the bone marrow, venous blood, and other body tissues. AML is the most predominant of leukemias occurring in adults (25%) and children (15-20%). The relapse after chemotherapy is a major concern in the treatment of AML. The overall 5-year survival rate in young AML patients is about 40-45% whereas in the elderly patients it is less than 10%. Leukemia stem-like cells (LSCs) having the ability to self-renew indefinitely, repopulate and persist longer in the G0/G1 phase play a crucial role in the AML relapse and refractoriness to chemotherapy. Hence, novel treatment strategies and diagnostic biomarkers targeting LSCs are being increasingly investigated. Through this review, we have explored the signaling modulations in the LSCs as the theragnostic targets. The significance of the self-renewal pathways in overcoming the treatment challenges in AML has been highlighted.
Collapse
Affiliation(s)
- Rahul Bhattacharjee
- KIIT School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT-DU), Bhubaneswar, Odisha, India
| | - Sharad Ghosh
- KIIT School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT-DU), Bhubaneswar, Odisha, India
| | - Arijit Nath
- KIIT School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT-DU), Bhubaneswar, Odisha, India
| | - Asmita Basu
- KIIT School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT-DU), Bhubaneswar, Odisha, India
| | - Ojaswi Biswas
- KIIT School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT-DU), Bhubaneswar, Odisha, India
| | - Chandragauda R Patil
- Department of Pharmacology, DIPSAR, Delhi Pharmaceutical Sciences and Research University, New Delhi, India
| | - Chanakya Nath Kundu
- KIIT School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT-DU), Bhubaneswar, Odisha, India.
| |
Collapse
|
|
37
|
Man Y, Lu Z, Yao X, Gong Y, Yang T, Wang Y. Recent Advancements in Poor Graft Function Following Hematopoietic Stem Cell Transplantation. Front Immunol 2022; 13:911174. [PMID: 35720412 PMCID: PMC9202575 DOI: 10.3389/fimmu.2022.911174] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Accepted: 05/06/2022] [Indexed: 01/05/2023] Open
Abstract
Poor graft function (PGF) is a life-threatening complication that occurs after transplantation and has a poor prognosis. With the rapid development of haploidentical hematopoietic stem cell transplantation, the pathogenesis of PGF has become an important issue. Studies of the pathogenesis of PGF have resulted in some success in CD34+-selected stem cell boosting. Mesenchymal stem cells, N-acetyl-l-cysteine, and eltrombopag have also been investigated as therapeutic strategies for PGF. However, predicting and preventing PGF remains challenging. Here, we propose that the seed, soil, and insect theories of aplastic anemia also apply to PGF; CD34+ cells are compared to seeds; the bone marrow microenvironment to soil; and virus infection, iron overload, and donor-specific anti-human leukocyte antigen antibodies to insects. From this perspective, we summarize the available information on the common risk factors of PGF, focusing on its potential mechanism. In addition, the safety and efficacy of new strategies for treating PGF are discussed to provide a foundation for preventing and treating this complex clinical problem.
Collapse
Affiliation(s)
- Yan Man
- Department of Hematology, National Key Clinical Specialty of Hematology, Yunnan Blood Disease Clinical Medical Center, Yunnan Blood Disease Hospital, The First People’s Hospital of Yunnan Province, Kunming, China
| | - Zhixiang Lu
- Department of Hematology, National Key Clinical Specialty of Hematology, Yunnan Blood Disease Clinical Medical Center, Yunnan Blood Disease Hospital, The First People’s Hospital of Yunnan Province, Kunming, China
| | - Xiangmei Yao
- Department of Hematology, National Key Clinical Specialty of Hematology, Yunnan Blood Disease Clinical Medical Center, Yunnan Blood Disease Hospital, The First People’s Hospital of Yunnan Province, Kunming, China
| | - Yuemin Gong
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing, China
| | - Tonghua Yang
- Department of Hematology, National Key Clinical Specialty of Hematology, Yunnan Blood Disease Clinical Medical Center, Yunnan Blood Disease Hospital, The First People’s Hospital of Yunnan Province, Kunming, China,*Correspondence: Tonghua Yang, ; Yajie Wang,
| | - Yajie Wang
- Department of Hematology, National Key Clinical Specialty of Hematology, Yunnan Blood Disease Clinical Medical Center, Yunnan Blood Disease Hospital, The First People’s Hospital of Yunnan Province, Kunming, China,*Correspondence: Tonghua Yang, ; Yajie Wang,
| |
Collapse
|
|
38
|
Gudmundsson KO, Du Y. Quiescence regulation by normal haematopoietic stem cells and leukaemia stem cells. FEBS J 2022. [PMID: 35514133 DOI: 10.1111/febs.16472] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 03/21/2022] [Accepted: 05/03/2022] [Indexed: 11/30/2022]
Abstract
The haematopoietic system is maintained by rare haematopoietic stem cells (HSCs), which are quiescent most of the time and only divide occasionally to self-renew and/or to undergo commitment to clonal expansion via the generation of highly proliferative progenitor cells. The latter is responsible for the generation of all mature cells of the system through subsequent lineage commitment and terminal differentiation. Cells with similar properties also exist in leukaemias and are known as leukaemia stem cells (LSCs). Quiescence provides essential protection for both HSC and LSC from cytotoxic stress and DNA damage and, in the case of LSCs, likely causes therapy resistance and disease relapse in leukaemia patients. Specific inhibition of LSC quiescence has been considered a promising strategy for eliminating LSCs and curing leukaemias. Although the understanding of mechanisms responsible for quiescence maintenance in these cells remains limited, particularly for LSCs, recent studies have suggested potential differences in their dependency on certain pathways and their levels of stress and DNA damage caused by increased cycling. Such differences likely stem from oncogenic mutations in LSCs and could be specifically exploited for the elimination of LSCs while sparing normal HSCs in the future.
Collapse
Affiliation(s)
- Kristbjorn Orri Gudmundsson
- Basic Science Program Leidos Biomedical Research Inc. Frederick National Laboratory for Cancer Research in the Mouse Cancer Genetics Program Center for Cancer Research NCI Frederick MD USA
| | - Yang Du
- Department of Pediatrics Uniformed Services University of the Health Sciences Bethesda MD USA
| |
Collapse
|
|
39
|
Fichtel P, von Bonin M, Kuhnert R, Möbus K, Bornhäuser M, Wobus M. Mesenchymal Stromal Cell-Derived Extracellular Vesicles Modulate Hematopoietic Stem and Progenitor Cell Viability and the Expression of Cell Cycle Regulators in an Age-dependent Manner. Front Bioeng Biotechnol 2022; 10:892661. [PMID: 35721867 PMCID: PMC9198480 DOI: 10.3389/fbioe.2022.892661] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 05/18/2022] [Indexed: 11/13/2022] Open
Abstract
Aging of the hematopoietic system is characterized by an expansion of hematopoietic stem and progenitor cells (HSPCs) with reduced capacity for engraftment, self-renewal, and lymphoid differentiation, resulting in myeloid-biased hematopoiesis. This process is mediated by both HSPC intrinsic and extrinsic factors, e.g., the stromal environment. A relevant cellular component of the bone marrow (BM) microenvironment are mesenchymal stromal cells (MSCs) which regulate fate and differentiation of HSPCs. The bi-directional communication with HSPCs is mediated either by direct cell-cell contacts or by extracellular vesicles (EVs) which carry bioactive substances such as small RNA, DNA, lipids and proteins. So far, the impact of MSC-derived EVs on human hematopoietic aging is poorly investigated. BM MSCs were isolated from young (n = 3, median age: 22 years) and aged (n = 3, median age: 70 years) donors and the EVs were isolated after culturing the confluent cell layer in serum-free medium for 48 h. CD34+ HSPCs were purified from peripheral blood of healthy donors (n = 3, median age: 65 years) by magnetic sorting. Nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM) and western blot detection of EV markers CD63, CD81 and Flotillin-1 revealed no significant differences between young and aged MSC-EVs. Interestingly, young MSCs secreted a significantly higher miRNA concentration than aged cells. However, the amount of distinct miRNAs such as miR-29a and miR-34a was significantly higher in aged MSC-EVs. HSPCs incubated with young EVs showed a significant increase in cell number and a higher viability. The expression of the tumor suppressors PTEN, a known target of mir-29a, and CDKN2A was increased in HSPCs incubated with young EVs. The clonogenic assay demonstrated a decreased colony number of CFU-GM after treatment with young EVs and an increased number of BFU-E/CFU-E after incubation with aged MSC-EVs. Xenogenic transplantation experiments showed no significant differences concerning the engraftment of lymphoid or myeloid cell compartments, but the overall human chimerism 8–16 weeks after transplantation was higher after EV treatment. In conclusion, our data suggest that HSPC characteristics such as cell cycle activity and clonogenicity can be modulated by MSC-derived EVs. Further studies have to elucidate the potential therapeutic relevance of our findings.
Collapse
Affiliation(s)
- Pascal Fichtel
- Department of Medicine I, University Hospital Carl Gustav Carus, Technische Universität, Dresden, Germany
| | - Malte von Bonin
- Department of Medicine I, University Hospital Carl Gustav Carus, Technische Universität, Dresden, Germany
| | - Robert Kuhnert
- Department of Medicine I, University Hospital Carl Gustav Carus, Technische Universität, Dresden, Germany
| | - Kristin Möbus
- Department of Medicine I, University Hospital Carl Gustav Carus, Technische Universität, Dresden, Germany
| | - Martin Bornhäuser
- Department of Medicine I, University Hospital Carl Gustav Carus, Technische Universität, Dresden, Germany
- Center for Regenerative Therapies, Technische Universität, Dresden, Germany
| | - Manja Wobus
- Department of Medicine I, University Hospital Carl Gustav Carus, Technische Universität, Dresden, Germany
- Center for Regenerative Therapies, Technische Universität, Dresden, Germany
- *Correspondence: Manja Wobus,
| |
Collapse
|
|
40
|
Lyu Y, Ge Y. Toward Elucidating Epigenetic and Metabolic Regulation of Stem Cell Lineage Plasticity in Skin Aging. Front Cell Dev Biol 2022; 10:903904. [PMID: 35663405 PMCID: PMC9160930 DOI: 10.3389/fcell.2022.903904] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 04/21/2022] [Indexed: 11/13/2022] Open
Abstract
Skin is the largest organ in human body, harboring a plethora of cell types and serving as the organismal barrier. Skin aging such as wrinkling and hair graying is graphically pronounced, and the molecular mechanisms behind these phenotypic manifestations are beginning to unfold. As in many other organs and tissues, epigenetic and metabolic deregulations have emerged as key aging drivers. Particularly in the context of the skin epithelium, the epigenome and metabolome coordinately shape lineage plasticity and orchestrate stem cell function during aging. Our review discusses recent studies that proposed molecular mechanisms that drive the degeneration of hair follicles, a major appendage of the skin. By focusing on skin while comparing it to model organisms and adult stem cells of other tissues, we summarize literature on genotoxic stress, nutritional sensing, metabolic rewiring, mitochondrial activity, and epigenetic regulations of stem cell plasticity. Finally, we speculate about the rejuvenation potential of rate-limiting upstream signals during aging and the dominant role of the tissue microenvironment in dictating aged epithelial stem cell function.
Collapse
Affiliation(s)
| | - Yejing Ge
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| |
Collapse
|
|
41
|
Wang R, Amoyel M. mRNA Translation Is Dynamically Regulated to Instruct Stem Cell Fate. Front Mol Biosci 2022; 9:863885. [PMID: 35433828 PMCID: PMC9008482 DOI: 10.3389/fmolb.2022.863885] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 02/25/2022] [Indexed: 12/12/2022] Open
Abstract
Stem cells preserve tissue homeostasis by replacing the cells lost through damage or natural turnover. Thus, stem cells and their daughters can adopt two identities, characterized by different programs of gene expression and metabolic activity. The composition and regulation of these programs have been extensively studied, particularly by identifying transcription factor networks that define cellular identity and the epigenetic changes that underlie the progressive restriction in gene expression potential. However, there is increasing evidence that post-transcriptional mechanisms influence gene expression in stem cells and their progeny, in particular through the control of mRNA translation. Here, we review the described roles of translational regulation in controlling all aspects of stem cell biology, from the decision to enter or exit quiescence to maintaining self-renewal and promoting differentiation. We focus on mechanisms controlling global translation rates in cells, mTOR signaling, eIF2ɑ phosphorylation, and ribosome biogenesis and how they allow stem cells to rapidly change their gene expression in response to tissue needs or environmental changes. These studies emphasize that translation acts as an additional layer of control in regulating gene expression in stem cells and that understanding this regulation is critical to gaining a full understanding of the mechanisms that underlie fate decisions in stem cells.
Collapse
Affiliation(s)
| | - Marc Amoyel
- Department of Cell and Developmental Biology, University College London, London, United Kingdom
| |
Collapse
|
|
42
|
Chen Z, Guo Q, Song G, Hou Y. Molecular regulation of hematopoietic stem cell quiescence. Cell Mol Life Sci 2022; 79:218. [PMID: 35357574 PMCID: PMC11072845 DOI: 10.1007/s00018-022-04200-w] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 02/07/2022] [Accepted: 02/07/2022] [Indexed: 12/19/2022]
Abstract
Hematopoietic stem cells (HSCs) are primarily dormant in a cell-cycle quiescence state to preserve their self-renewal capacity and long-term maintenance, which is essential for the homeostasis of hematopoietic system. Dysregulation of quiescence causes HSC dysfunction and may result in aberrant hematopoiesis (e.g., myelodysplastic syndrome and bone marrow failure syndromes) and leukemia transformation. Accumulating evidence indicates that both intrinsic molecular networks and extrinsic signals regulate HSC quiescence, including cell-cycle regulators, transcription factors, epigenetic factors, and niche factors. Further, the transition between quiescence and activation of HSCs is a continuous developmental path driven by cell metabolism (e.g., protein synthesis, glycolysis, oxidative phosphorylation, and autophagy). Elucidating the complex regulatory networks of HSC quiescence will expand the knowledge of HSC hemostasis and benefit for clinical HSC use. Here, we review the current understanding and progression on the molecular and metabolic regulation of HSC quiescence, providing a more complete picture regarding the mechanisms of HSC quiescence maintenance.
Collapse
Affiliation(s)
- Zhe Chen
- Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016, China
- Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Qian Guo
- Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016, China
- Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Guanbin Song
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, China.
| | - Yu Hou
- Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016, China.
- Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
| |
Collapse
|
|
43
|
ROCK ‘n TOR: An Outlook on Keratinocyte Stem Cell Expansion in Regenerative Medicine via Protein Kinase Inhibition. Cells 2022; 11:cells11071130. [PMID: 35406693 PMCID: PMC8997668 DOI: 10.3390/cells11071130] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 03/23/2022] [Accepted: 03/24/2022] [Indexed: 12/13/2022] Open
Abstract
Keratinocyte stem cells play a fundamental role in homeostasis and repair of stratified epithelial tissues. Transplantation of cultured keratinocytes autografts provides a landmark example of successful cellular therapies by restoring durable integrity in stratified epithelia lost to devastating tissue conditions. Despite the overall success of such procedures, failures still occur in case of paucity of cultured stem cells in therapeutic grafts. Strategies aiming at a further amplification of stem cells during keratinocyte ex vivo expansion may thus extend the applicability of these treatments to subjects in which endogenous stem cells pools are depauperated by aging, trauma, or disease. Pharmacological targeting of stem cell signaling pathways is recently emerging as a powerful strategy for improving stem cell maintenance and/or amplification. Recent experimental data indicate that pharmacological inhibition of two prominent keratinocyte signaling pathways governed by apical mTOR and ROCK protein kinases favor stem cell maintenance and/or amplification ex vivo and may improve the effectiveness of stem cell-based therapeutic procedures. In this review, we highlight the pathophysiological roles of mTOR and ROCK in keratinocyte biology and evaluate existing pre-clinical data on the effects of their inhibition in epithelial stem cell expansion for transplantation purposes.
Collapse
|
|
44
|
Cuesta-Casanovas L, Delgado-Martínez J, Cornet-Masana JM, Carbó JM, Clément-Demange L, Risueño RM. Lysosome-mediated chemoresistance in acute myeloid leukemia. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2022; 5:233-244. [PMID: 35582535 PMCID: PMC8992599 DOI: 10.20517/cdr.2021.122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Despite the outstanding advances in understanding the biology underlying the pathophysiology of acute myeloid leukemia (AML) and the promising preclinical data published lastly, AML treatment still relies on a classic chemotherapy regimen largely unchanged for the past five decades. Recently, new drugs have been approved for AML, but the real clinical benefit is still under evaluation. Nevertheless, primary refractory and relapse AML continue to represent the main clinical challenge, as the majority of AML patients will succumb to the disease despite achieving a complete remission during the induction phase. As such, treatments for chemoresistant AML represent an unmet need in this disease. Although great efforts have been made to decipher the biological basis for leukemogenesis, the mechanism by which AML cells become resistant to chemotherapy is largely unknown. The identification of the signaling pathways involved in resistance may lead to new combinatory therapies or new therapeutic approaches suitable for this subset of patients. Several mechanisms of chemoresistance have been identified, including drug transporters, key secondary messengers, and metabolic regulators. However, no therapeutic approach targeting chemoresistance has succeeded in clinical trials, especially due to broad secondary effects in healthy cells. Recent research has highlighted the importance of lysosomes in this phenomenon. Lysosomes' key role in resistance to chemotherapy includes the potential to sequester drugs, central metabolic signaling role, and gene expression regulation. These results provide further evidence to support the development of new therapeutic approaches that target lysosomes in AML.
Collapse
Affiliation(s)
- Laia Cuesta-Casanovas
- Josep Carreras Leukaemia Research Institute (IJC), Barcelona 08916, Spain
- Faculty of Biosciences, Autonomous University of Barcelona, Bellaterra (Cerdanyola del Vallès) 08193, Spain
| | - Jennifer Delgado-Martínez
- Josep Carreras Leukaemia Research Institute (IJC), Barcelona 08916, Spain
- Faculty of Pharmacy, University of Barcelona, Barcelona 08028, Spain
| | | | - José M. Carbó
- Leukos Biotech, Muntaner, 383, Barcelona 08036, Spain
| | | | - Ruth M. Risueño
- Josep Carreras Leukaemia Research Institute (IJC), Barcelona 08916, Spain
| |
Collapse
|
|
45
|
Abstract
Metabolism has been studied mainly in cultured cells or at the level of whole tissues or whole organisms in vivo. Consequently, our understanding of metabolic heterogeneity among cells within tissues is limited, particularly when it comes to rare cells with biologically distinct properties, such as stem cells. Stem cell function, tissue regeneration and cancer suppression are all metabolically regulated, although it is not yet clear whether there are metabolic mechanisms unique to stem cells that regulate their activity and function. Recent work has, however, provided evidence that stem cells do have a metabolic signature that is distinct from that of restricted progenitors and that metabolic changes influence tissue homeostasis and regeneration. Stem cell maintenance throughout life in many tissues depends upon minimizing anabolic pathway activation and cell division. Consequently, stem cell activation by tissue injury is associated with changes in mitochondrial function, lysosome activity and lipid metabolism, potentially at the cost of eroding self-renewal potential. Stem cell metabolism is also regulated by the environment: stem cells metabolically interact with other cells in their niches and are able to sense and adapt to dietary changes. The accelerating understanding of stem cell metabolism is revealing new aspects of tissue homeostasis with the potential to promote tissue regeneration and cancer suppression.
Collapse
|
|
46
|
A Long Journey before Cycling: Regulation of Quiescence Exit in Adult Muscle Satellite Cells. Int J Mol Sci 2022; 23:ijms23031748. [PMID: 35163665 PMCID: PMC8836154 DOI: 10.3390/ijms23031748] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 01/28/2022] [Accepted: 01/30/2022] [Indexed: 02/04/2023] Open
Abstract
Skeletal muscle harbors a pool of stem cells called muscle satellite cells (MuSCs) that are mainly responsible for its robust regenerative capacities. Adult satellite cells are mitotically quiescent in uninjured muscles under homeostasis, but they exit quiescence upon injury to re-enter the cell cycle to proliferate. While most of the expanded satellites cells differentiate and fuse to form new myofibers, some undergo self-renewal to replenish the stem cell pool. Specifically, quiescence exit describes the initial transition of MuSCs from quiescence to the first cell cycle, which takes much longer than the time required for subsequent cell cycles and involves drastic changes in cell size, epigenetic and transcriptomic profiles, and metabolic status. It is, therefore, an essential period indispensable for the success of muscle regeneration. Diverse mechanisms exist in MuSCs to regulate quiescence exit. In this review, we summarize key events that occur during quiescence exit in MuSCs and discuss the molecular regulation of this process with an emphasis on multiple levels of intrinsic regulatory mechanisms. A comprehensive understanding of how quiescence exit is regulated will facilitate satellite cell-based muscle regenerative therapies and advance their applications in various disease and aging conditions.
Collapse
|
|
47
|
Wang C, Ning H, Gao J, Xue T, Zhao M, Jiang X, Zhu X, Guo X, Li H, Wang X. Disruption of hematopoiesis attenuates the osteogenic differentiation capacity of bone marrow stromal cells. Stem Cell Res Ther 2022; 13:27. [PMID: 35073981 PMCID: PMC8785551 DOI: 10.1186/s13287-022-02708-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 10/07/2021] [Indexed: 12/18/2022] Open
Abstract
Background The homeostasis of mesenchymal stem cells (MSCs) is modulated by both their own intracellular molecules and extracellular milieu signals. Hematopoiesis in the bone marrow is maintained by niche cells, including MSCs, and it is indispensable for life. The role of MSCs in maintaining hematopoietic homeostasis has been fully elucidated. However, little is known about the mechanism by which hematopoietic cells reciprocally regulate niche cells. The present study aimed to explore the close relationship between MSCs and hematopoietic cells, which may be exploited for the development of new therapeutic strategies for related diseases. Methods In this study, we isolated cells from the offspring of Tie2Cre + and Ptenflox/flox mice. After cell isolation and culture, we investigated the effect of hematopoietic cells on MSCs using various methods, including flow cytometry, adipogenic and osteogenic differentiation analyses, quantitative PCR, western bloting, and microCT analysis. Results Our results showed that when the phosphatase and tensin homolog deleted on chromosome 10 (Pten) gene was half-deleted in hematopoietic cells, hematopoiesis and osteogenesis were normal in young mice; the frequency of erythroid progenitor cells in the bone marrow gradually decreased and osteogenesis in the femoral epiphysis weakened as the mice grew. The heterozygous loss of Pten in hematopoietic cells leads to the attenuation of osteogenic differentiation and enhanced adipogenic differentiation of MSCs in vitro. Co-culture with normal hematopoietic cells rescued the abnormal differentiation of MSCs, and in contrast, MSCs co-cultured with heterozygous null Pten hematopoietic cells showed abnormal differentiation activity. Co-culture with erythroid progenitor cells also revealed them to play an important role in MSC differentiation. Conclusion Our data suggest that hematopoietic cells function as niche cells of MSCs to balance the differentiation activity of MSCs and may ultimately affect bone development.
Collapse
Affiliation(s)
- Changzhen Wang
- The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing, 100850, China. .,Laboratory of Bioelectromagnetics, Beijing Institute of Radiation and Medicine, 27 Taiping Road, Haidian District, Beijing, 100850, China.
| | - Hongmei Ning
- Department of Hematology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100071, China
| | - Jiao Gao
- The Chinese People's Liberation Army Strategic Support Force Characteristic Medical Center, Beijing, 100101, China
| | - Teng Xue
- Laboratory of Bioelectromagnetics, Beijing Institute of Radiation and Medicine, 27 Taiping Road, Haidian District, Beijing, 100850, China
| | - Ming Zhao
- The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing, 100850, China
| | - Xiaoxia Jiang
- The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing, 100850, China
| | - Xiaoming Zhu
- The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing, 100850, China
| | - Ximin Guo
- The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing, 100850, China
| | - Hong Li
- The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing, 100850, China
| | - Xiaoyan Wang
- The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing, 100850, China.
| |
Collapse
|
|
48
|
Temporal Gene Expression Profiles Reflect the Dynamics of Lymphoid Differentiation. Int J Mol Sci 2022; 23:ijms23031115. [PMID: 35163045 PMCID: PMC8834919 DOI: 10.3390/ijms23031115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 01/10/2022] [Accepted: 01/16/2022] [Indexed: 02/01/2023] Open
Abstract
Understanding the emergence of lymphoid committed cells from multipotent progenitors (MPP) is a great challenge in hematopoiesis. To gain deeper insight into the dynamic expression changes associated with these transitions, we report the quantitative transcriptome of two MPP subsets and the common lymphoid progenitor (CLP). While the transcriptome is rather stable between MPP2 and MPP3, expression changes increase with differentiation. Among those, we found that pioneer lymphoid genes such as Rag1, Mpeg1, and Dntt are expressed continuously from MPP2. Others, such as CD93, are CLP specific, suggesting their potential use as new markers to improve purification of lymphoid populations. Notably, a six-transcription factor network orchestrates the lymphoid differentiation program. Additionally, we pinpointed 24 long intergenic-non-coding RNA (lincRNA) differentially expressed through commitment and further identified seven novel forms. Collectively, our approach provides a comprehensive landscape of coding and non-coding transcriptomes expressed during lymphoid commitment.
Collapse
|
|
49
|
Davis AG, Johnson DT, Zheng D, Wang R, Jayne ND, Liu M, Shin J, Wang L, Stoner SA, Zhou JH, Ball ED, Tian B, Zhang DE. Alternative polyadenylation dysregulation contributes to the differentiation block of acute myeloid leukemia. Blood 2022; 139:424-438. [PMID: 34482400 PMCID: PMC8777198 DOI: 10.1182/blood.2020005693] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 08/16/2021] [Indexed: 01/22/2023] Open
Abstract
Posttranscriptional regulation has emerged as a driver for leukemia development and an avenue for therapeutic targeting. Among posttranscriptional processes, alternative polyadenylation (APA) is globally dysregulated across cancer types. However, limited studies have focused on the prevalence and role of APA in myeloid leukemia. Furthermore, it is poorly understood how altered poly(A) site usage of individual genes contributes to malignancy or whether targeting global APA patterns might alter oncogenic potential. In this study, we examined global APA dysregulation in patients with acute myeloid leukemia (AML) by performing 3' region extraction and deep sequencing (3'READS) on a subset of AML patient samples along with healthy hematopoietic stem and progenitor cells (HSPCs) and by analyzing publicly available data from a broad AML patient cohort. We show that patient cells exhibit global 3' untranslated region (UTR) shortening and coding sequence lengthening due to differences in poly(A) site (PAS) usage. Among APA regulators, expression of FIP1L1, one of the core cleavage and polyadenylation factors, correlated with the degree of APA dysregulation in our 3'READS data set. Targeting global APA by FIP1L1 knockdown reversed the global trends seen in patients. Importantly, FIP1L1 knockdown induced differentiation of t(8;21) cells by promoting 3'UTR lengthening and downregulation of the fusion oncoprotein AML1-ETO. In non-t(8;21) cells, FIP1L1 knockdown also promoted differentiation by attenuating mechanistic target of rapamycin complex 1 (mTORC1) signaling and reducing MYC protein levels. Our study provides mechanistic insights into the role of APA in AML pathogenesis and indicates that targeting global APA patterns can overcome the differentiation block in patients with AML.
Collapse
Affiliation(s)
- Amanda G Davis
- Moores Cancer Center and
- Division of Biological Sciences, University of California San Diego, La Jolla, CA
| | - Daniel T Johnson
- Moores Cancer Center and
- Division of Biological Sciences, University of California San Diego, La Jolla, CA
| | - Dinghai Zheng
- Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers New Jersey Medical School, Newark, NJ
| | - Ruijia Wang
- Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers New Jersey Medical School, Newark, NJ
| | - Nathan D Jayne
- Moores Cancer Center and
- Division of Biological Sciences, University of California San Diego, La Jolla, CA
| | - Mengdan Liu
- Moores Cancer Center and
- Division of Biological Sciences, University of California San Diego, La Jolla, CA
| | - Jihae Shin
- Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers New Jersey Medical School, Newark, NJ
| | - Luyang Wang
- Program in Gene Expression and Regulation, Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, PA
| | | | - Jie-Hua Zhou
- Division of Blood and Marrow Transplantation, Department of Medicine; and
| | - Edward D Ball
- Division of Blood and Marrow Transplantation, Department of Medicine; and
| | - Bin Tian
- Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers New Jersey Medical School, Newark, NJ
- Program in Gene Expression and Regulation, Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, PA
| | - Dong-Er Zhang
- Moores Cancer Center and
- Division of Biological Sciences, University of California San Diego, La Jolla, CA
- Department of Pathology, University of California San Diego, La Jolla, CA
| |
Collapse
|
|
50
|
Okeke C, Silas U, Nnodu O, Clementina O. HSC and miRNA Regulation with Implication for Foetal Haemoglobin Induction in Beta Haemoglobinopathies. Curr Stem Cell Res Ther 2022; 17:339-347. [PMID: 35189805 DOI: 10.2174/1574888x17666220221104711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 11/29/2021] [Accepted: 12/08/2021] [Indexed: 11/22/2022]
Abstract
Sickle cell disease (SCD) is one of the most common haemoglobinopathies worldwide, with up to 70 % of global SCD annual births occurring in sub-Saharan Africa. Reports have shown that 50 to 80 % of affected children in these countries die annually. Efforts geared towards understanding and controlling HbF production in SCD patients could lead to strategies for effective control of globin gene expression and therapeutic approaches that could be beneficial to individuals with haemoglobinopathies. Hemopoietic stem cells (HSCs) are characterized by a specific miRNA signature in every state of differentiation. The role of miRNAs has become evident both in the maintenance of the "stemness" and in the early induction of differentiation by modulation of the expression of the master pluripotency genes and during early organogenesis. miRNAs are extra regulatory mechanisms in hematopoietic stem cells (HSCs) via influencing transcription profiles together with transcript stability. miRNAs have been reported to be used to reprogram primary somatic cells toward pluripotency. Their involvement in cell editing holds the potential for therapy for many genetic diseases. This review provides a snapshot of miRNA involvement in cell fate decisions, haemoglobin induction pathway, and their journey as some emerge prime targets for therapy in beta haemoglobinopathies.
Collapse
Affiliation(s)
- Chinwe Okeke
- Department of Medical Laboratory Science, Faculty of Health Science and Technology, University of Nigeria, Nsukka, Nigeria
| | - Ufele Silas
- Department of Medical Laboratory Science, Faculty of Health Science and Technology, University of Nigeria, Nsukka, Nigeria
| | - Obiageli Nnodu
- Department of Haematology, College of Medicine, University of Abuja, Abuja Nigeria
| | - Odoh Clementina
- Department of Medical Laboratory Science, Faculty of Health Science and Technology, University of Nigeria, Nsukka, Nigeria
| |
Collapse
|