|
1
|
Pimentel A, Gonçalves-Silva T, Jasmin, Mendez-Otero R. Isolation and characterization of canine umbilical cord mesenchymal/stromal stem cells. In Vitro Cell Dev Biol Anim 2025; 61:472-485. [PMID: 40325278 DOI: 10.1007/s11626-025-01023-4] [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: 11/05/2024] [Accepted: 01/30/2025] [Indexed: 05/07/2025]
Abstract
Mesenchymal stem cells (MSCs) have therapeutic potential due to their immunomodulatory and anti-inflammatory properties. In veterinary medicine, adipose tissue is the most common source of MSCs to treat canine disease, but the collection process is invasive, and the cells are influenced by the age and health conditions of the donor. These problems enhance interest in seeking alternative MSC sources, such as perinatal tissues. In this study, we developed and validated an optimized protocol for isolating canine umbilical cord MSCs for application in veterinary therapies. Umbilical cords obtained from cesarean sections were processed using three different protocols, involving combinations of mechanical and enzymatic tissue dissociation. The cells were cultured and evaluated for membrane receptors by flow cytometry to identify MSCs and assessed for their differentiation capacity. The number of cells obtained did not differ significantly between the combined protocol with trypsin and collagenase (TRIP + COL) and the collagenase protocol (COL). In in vitro culture, the combined TRIP + COL and COL yielded 12 to 14 times more cells, respectively, in the first passage than the explant (EXP) group, within fewer days of culture. Additionally, the cells obtained from these protocols showed a greater capacity for expansion over passages, and cells from both protocols showed fibroblast-like morphology and proliferation capacity up to the sixth passage. The cells obtained from these protocols were characterized by phenotype: CD45-, CD34-, CD14-, HLA-DR-, CD29+, CD44+, and CD90+, consistent with MSC identity. However, CD90 expression in the cells decreased significantly at sixth passage. Regarding differentiation, cells obtained from the COL protocol showed a capacity for commitment to the chondrogenic and osteogenic lineages. In conclusion, the COL and TRIP + COL protocols were more effective than the EXP protocol in terms of both the number and quality of isolated cells. However, due to its less-aggressive enzymatic nature, we considered the COL protocol to be the best method to obtain canine MSCs.
Collapse
Affiliation(s)
- Aline Pimentel
- Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro (IBCCF-UFRJ), Av. Carlos Chagas Filho, 373, Rio de Janeiro, RJ 21941-170, Brazil.
| | - Triciana Gonçalves-Silva
- National Center for Structural Biology and Bioimaging, Federal University of Rio de Janeiro (CENABIO-UFRJ), Av. Carlos Chagas Filho, 373, Rio de Janeiro, RJ 21941-170, Brazil
| | - Jasmin
- Duque de Caxias Campus, NUMPEX-Bio, Federal University of Rio de Janeiro, Estrada de Xerém, 27 - Xerém, Duque de Caxias, RJ 25245-390, Brazil
| | - Rosalia Mendez-Otero
- Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro (IBCCF-UFRJ), Av. Carlos Chagas Filho, 373, Rio de Janeiro, RJ 21941-170, Brazil
| |
Collapse
|
|
2
|
Allouh MZ, Rizvi SFA, Alamri A, Jimoh Y, Aouda S, Ouda ZH, Hamad MIK, Perez-Cruet M, Chaudhry GR. Mesenchymal stromal/stem cells from perinatal sources: biological facts, molecular biomarkers, and therapeutic promises. Stem Cell Res Ther 2025; 16:127. [PMID: 40055783 PMCID: PMC11889844 DOI: 10.1186/s13287-025-04254-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 02/25/2025] [Indexed: 05/13/2025] Open
Abstract
The use of mesenchymal stem cells (MSCs) from perinatal tissue sources has gained attention due to their availability and lack of significant ethical or moral concerns. These cells have a higher proliferative capability than adult MSCs and less immunogenic or tumorigenesis risk than fetal and embryonic stem cells. Additionally, they do not require invasive isolation methods like fetal and adult MSCs. We reviewed the main biological and therapeutic aspects of perinatal MSCs in a three-part article. In the first part, we revised the main biological features and characteristics of MSCs and the advantages of perinatal MSCs over other types of SCs. In the second part, we provided a detailed molecular background for the main biomarkers that can be used to identify MSCs. In the final part, we appraised the therapeutic application of perinatal MSCs in four major degenerative disorders: degenerative disc disease, retinal degenerative diseases, ischemic heart disease, and neurodegenerative diseases. In conclusion, there is no single specific molecular marker to identify MSCs. We recommend using at least two positive markers of stemness (CD29, CD73, CD90, or CD105) and two negative markers (CD34, CD45, or CD14) to exclude the hematopoietic origin. Moreover, utilizing perinatal MSCs for managing degenerative diseases presents a promising therapeutic approach. This review emphasizes the significance of employing more specialized progenitor cells that originated from the perinatal MSCs. The review provides scientific evidence from the literature that applying these progenitor cells in therapeutic procedures provides a greater regenerative capacity than the original primitive MSCs. Finally, this review provides a valuable reference for researchers exploring perinatal MSCs and their therapeutic applications.
Collapse
Affiliation(s)
- Mohammed Z Allouh
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, P. O. Box: 15551, Al Ain, UAE.
- OU-WB Institute for Stem Cell and Regenerative Medicine, Oakland University, Rochester, MI, 48309, USA.
| | - Syed Faizan Ali Rizvi
- OU-WB Institute for Stem Cell and Regenerative Medicine, Oakland University, Rochester, MI, 48309, USA
- Department of Biological Sciences, Oakland University, Rochester, MI, 48309, USA
| | - Ali Alamri
- OU-WB Institute for Stem Cell and Regenerative Medicine, Oakland University, Rochester, MI, 48309, USA
- Department of Biological Sciences, Oakland University, Rochester, MI, 48309, USA
| | - Yusuf Jimoh
- OU-WB Institute for Stem Cell and Regenerative Medicine, Oakland University, Rochester, MI, 48309, USA
- Department of Biological Sciences, Oakland University, Rochester, MI, 48309, USA
| | - Salma Aouda
- College of Medicine and Health Sciences, Khalifa University, Abu Dhabi, UAE
| | - Zakaria H Ouda
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, P. O. Box: 15551, Al Ain, UAE
| | - Mohammad I K Hamad
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, P. O. Box: 15551, Al Ain, UAE
| | - Mick Perez-Cruet
- OU-WB Institute for Stem Cell and Regenerative Medicine, Oakland University, Rochester, MI, 48309, USA
- Department of Neurosurgery, Corewell Health, Royal Oak, MI, USA
| | - G Rasul Chaudhry
- OU-WB Institute for Stem Cell and Regenerative Medicine, Oakland University, Rochester, MI, 48309, USA.
- Department of Biological Sciences, Oakland University, Rochester, MI, 48309, USA.
| |
Collapse
|
|
3
|
Tsunematsu T, Mouri Y, Shao W, Arakaki R, Ruppert JG, Murano K, Ishimaru N, Guardavaccaro D, Pagano M, Kudo Y. Sustained chromosomal passenger complex activity preserves the pluripotency of human embryonic carcinoma cells. Sci Signal 2025; 18:eadg4626. [PMID: 40136047 DOI: 10.1126/scisignal.adg4626] [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: 08/08/2023] [Accepted: 01/30/2025] [Indexed: 03/27/2025]
Abstract
Human embryonic carcinoma (hEC) cells are derived from teratocarcinomas, exhibit robust proliferation, have a high differentiation potential, are the malignant counterparts of human embryonic stem cells (hESCs), and are considered hESC-like. The chromosomal passenger complex (CPC), made up of the microtuble binding protein Borealin, the kinase Aurora-B, the CPC-stabilizing inner centromere protein (INCENP), and the inhibitor of apoptosis family member Survivin, regulates cell division and is active exclusively during mitosis in somatic cells. The anaphase-promoting complex/cyclosome and its cofactor Cdh1 (APC/CCdh1) is a ubiquitylating complex that catalyzes the degradation of Aurora-B and Borealin in somatic cells but has low activity during interphase in hESCs. Here, we found that Borealin and Aurora-B exhibited sustained stability throughout the cell cycle of hEC cells due to low APC/CCdh1 activity. In contrast with somatic cells, CPC activity persisted across the cell cycle of hEC cells because of diminished APC/CCdh1 activity. Disrupting the CPC complex by depleting its constituents triggered spontaneous differentiation in hEC cells. As hEC cells differentiated, APC/CCdh1 activation curtailed CPC activity. Inactivating the CPC by pharmacologically inhibiting Aurora-B induced hEC cell differentiation by activating the epithelial-to-mesenchymal transition (EMT) program. Hence, APC/CCdh1-mediated termination of CPC activity triggered hEC cell differentiation. Collectively, these findings demonstrate a role for the CPC in governing hESC cell fate.
Collapse
Affiliation(s)
- Takaaki Tsunematsu
- Department of Oral Molecular Pathology, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8504, Japan
| | - Yasuhiro Mouri
- Department of Oral Bioscience, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8504, Japan
| | - Wenhua Shao
- Department of Oral Bioscience, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8504, Japan
| | - Rieko Arakaki
- Department of Oral Molecular Pathology, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8504, Japan
| | - Jan G Ruppert
- Wellcome Centre for Cell Biology, Institute of Cell Biology, University of Edinburgh, Edinburgh EH9 3BF, Scotland, UK
| | - Kensaku Murano
- Department of Molecular Biology, Keio University School of Medicine, Tokyo, Japan
| | - Naozumi Ishimaru
- Department of Oral Molecular Pathology, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8504, Japan
| | | | - Michele Pagano
- Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, NY 10016, USA
- NYU Perlmutter Cancer Center, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, NY 10016, USA
- Howard Hughes Medical Institute, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, NY 10016, USA
| | - Yasusei Kudo
- Department of Oral Bioscience, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8504, Japan
| |
Collapse
|
|
4
|
Yan WT, Wang JS, Fan PZ, Roberts S, Wright K, Zhang ZZ. The clinical potential of meniscal progenitor cells. THE JOURNAL OF CARTILAGE & JOINT PRESERVATION 2024; 4:None. [PMID: 39669533 PMCID: PMC11636529 DOI: 10.1016/j.jcjp.2024.100166] [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] [Received: 09/28/2023] [Revised: 01/29/2024] [Accepted: 02/11/2024] [Indexed: 12/14/2024]
Abstract
Introduction The meniscus is an important cushioning structure of the knee joint, with the maintenance of its normal structure and function playing a crucial role in protecting the joint from early degeneration. Stem/progenitor cells could be the key to help researchers to have a deeper understanding of the biological process of meniscal injury repair and may be important in the meniscus tissue regeneration processes. To the best of our knowledge, there is currently a lack of comprehensive reviews on existing research about the meniscus progenitor cells (MPCs). Objectives By reviewing the existing MPC literature, we aim to provide insights for future research on meniscus regeneration. Methods The isolation methods, biological characteristics and the translational application of MPCs were summarized. Results MPCs could be isolated according to their colony-forming ability, marker expression, migration ability, and differential adhesion to fibronectin. Most existing studies on surface markers of MPCs have largely followed the paradigm of mesenchymal stromal/stem cell research. Based on the information provided by their surface markers and expression profile, researchers located MPCs in the peripheral surface area of the meniscus. Few researches have investigated the translation and application of MPCs, with most studies being limited to MPCs extraction and subsequent reimplantation in vivo. Conclusions MPCs are a group of meniscus-resident cells, which exhibit certain stem/progenitor cell characteristics, such as the ability to undergo multilineage differentiation in in vitro culture.
Collapse
Affiliation(s)
- Wan-Ting Yan
- Department of Sports Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jing-Song Wang
- Department of Sports Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | | | - Sally Roberts
- Spinal Studies & Cartilage Research Group, Robert Jones and Agnes Hunt Orthopaedic Hospital NHS Trust, Oswestry, United Kingdom
- School of Pharmacy and Bioengineering, Keele University, Staffordshire, United Kingdom
| | - Karina Wright
- Spinal Studies & Cartilage Research Group, Robert Jones and Agnes Hunt Orthopaedic Hospital NHS Trust, Oswestry, United Kingdom
- School of Pharmacy and Bioengineering, Keele University, Staffordshire, United Kingdom
| | - Zheng-Zheng Zhang
- Department of Sports Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| |
Collapse
|
|
5
|
Aboushousha T, Osama M, Mohamed M, Khaled Y, Elmeligy HA, Ossama Y. Significance of CD70, VEGF, and CD90 Immunohistochemical Expression in Colorectal Cancer. Asian Pac J Cancer Prev 2024; 25:3691-3699. [PMID: 39471037 PMCID: PMC11711364 DOI: 10.31557/apjcp.2024.25.10.3691] [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: 06/13/2024] [Accepted: 10/12/2024] [Indexed: 11/01/2024] Open
Abstract
BACKGROUND Colorectal cancer is the 4th most reported reason for cancer death worldwide. It is a complex and multifaceted disease with diverse histopathological manifestations. CD70 is present on activated immune cells and is upregulated in patients who have finished adjuvant therapy. VEGF controls angiogenesis and demonstrates immuno-regulatory characteristics that inhibit the anticancer activity of immune cells. CD90 is an extracellular cancer stem cell marker and regulates apoptosis, cell migration, and T cell activation. AIM OF WORK to elucidate the prognostic potential of a combined immunohistochemical assessment of CD70, VEGF, and CD90 biomarkers in colorectal cancer tissues. MATERIALS AND METHODS Our study is a retrospective study done on 70 paraffin blocks (45 colorectal carcinoma cases and 11 adenomas, along with 14 cases of colitis serving as controls) were subjected to conventional Hematoxylin and Eosin stain for routine histopathological assessment and immunohistochemical staining for CD70, VEGF and CD90. Our investigation focused on evaluating the expression of CD70, VEGF, and CD90 in various colorectal tissues, including colitis, adenomas, and adenocarcinomas, as well as different grades of adenocarcinoma tissues, different stages of tumor invasiveness, and lymph node status. RESULTS Our research revealed distinctive expression patterns of CD70, VEGF, and CD90 across different stages and grades of colorectal cancer. CONCLUSION our research signifies the potential clinical utility of the CD70, VEGF, and CD90 triad as prognostic markers in colorectal cancer. The combined analysis of these markers emerged as a potent prognostic tool, offering valuable insights into disease progression. Our research showed that epithelial CD90 is the most sensitive marker for both tumor stage and lymph node status. CD70 and VEGF showed a statistically significant relation with lymph node status only and not with tumor stage.
Collapse
Affiliation(s)
- Tarek Aboushousha
- Department of Pathology, Theodor Bilharz Research Institute, Giza, Egypt.
| | - Merna Osama
- Faculty of Biotechnology, October University of Modern Science and Arts, Giza, Egypt.
| | - Merna Mohamed
- Faculty of Biotechnology, October University of Modern Science and Arts, Giza, Egypt.
| | - Yasmine Khaled
- Faculty of Biotechnology, October University of Modern Science and Arts, Giza, Egypt.
| | - Hesham A Elmeligy
- Department of Surgery, Theodor Bilharz Research Institute, Giza, Egypt.
| | - Yousra Ossama
- Department of Pathology, October 6 University, Giza, Egypt.
| |
Collapse
|
|
6
|
Guo T, Xu J. Cancer-associated fibroblasts: a versatile mediator in tumor progression, metastasis, and targeted therapy. Cancer Metastasis Rev 2024; 43:1095-1116. [PMID: 38602594 PMCID: PMC11300527 DOI: 10.1007/s10555-024-10186-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Accepted: 03/31/2024] [Indexed: 04/12/2024]
Abstract
Tumor microenvironment (TME) has been demonstrated to play a significant role in tumor initiation, progression, and metastasis. Cancer-associated fibroblasts (CAFs) are the major component of TME and exhibit heterogeneous properties in their communication with tumor cells. This heterogeneity of CAFs can be attributed to various origins, including quiescent fibroblasts, mesenchymal stem cells (MSCs), adipocytes, pericytes, endothelial cells, and mesothelial cells. Moreover, single-cell RNA sequencing has identified diverse phenotypes of CAFs, with myofibroblastic CAFs (myCAFs) and inflammatory CAFs (iCAFs) being the most acknowledged, alongside newly discovered subtypes like antigen-presenting CAFs (apCAFs). Due to these heterogeneities, CAFs exert multiple functions in tumorigenesis, cancer stemness, angiogenesis, immunosuppression, metabolism, and metastasis. As a result, targeted therapies aimed at the TME, particularly focusing on CAFs, are rapidly developing, fueling the promising future of advanced tumor-targeted therapy.
Collapse
Affiliation(s)
- Tianchen Guo
- Women's Reproductive Health Laboratory of Zhejiang Province, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang, China
| | - Junfen Xu
- Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang, China.
| |
Collapse
|
|
7
|
Soul J, Carlsson E, Hofmann SR, Russ S, Hawkes J, Schulze F, Sergon M, Pablik J, Abraham S, Hedrich CM. Tissue gene expression profiles and communication networks inform candidate blood biomarker identification in psoriasis and atopic dermatitis. Clin Immunol 2024; 265:110283. [PMID: 38880200 DOI: 10.1016/j.clim.2024.110283] [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: 02/18/2024] [Revised: 05/24/2024] [Accepted: 06/10/2024] [Indexed: 06/18/2024]
Abstract
Overlapping clinical and pathomechanistic features can complicate the diagnosis and treatment of inflammatory skin diseases, including psoriasis and atopic dermatitis (AD). Spatial transcriptomics allows the identification of disease- and cell-specific molecular signatures that may advance biomarker development and future treatments. This study identified transcriptional signatures in keratinocytes and sub-basal CD4+ and CD8+ T lymphocytes from patients with psoriasis and AD. In silico prediction of ligand:receptor interactions delivered key signalling pathways (interferon, effector T cells, stroma cell and matrix biology, neuronal development, etc.). Targeted validation of selected transcripts, including CCL22, RELB, and JUND, in peripheral blood T cells suggests the chosen approach as a promising tool also in other inflammatory diseases. Psoriasis and AD are characterized by transcriptional dysregulation in T cells and keratinocytes that may be targeted therapeutically. Spatial transcriptomics is a valuable tool in the search for molecular signatures that can be used as biomarkers and/or therapeutic targets.
Collapse
Affiliation(s)
- J Soul
- Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom
| | - E Carlsson
- Department of Women's & Children's Health, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom
| | - S R Hofmann
- Department of Pediatrics, Universitätsklinikum Carl Gustav Carus, TU Dresden, Dresden, Germany
| | - S Russ
- Department of Pediatrics, Universitätsklinikum Carl Gustav Carus, TU Dresden, Dresden, Germany
| | - J Hawkes
- Department of Women's & Children's Health, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom
| | - F Schulze
- Department of Pediatrics, Universitätsklinikum Carl Gustav Carus, TU Dresden, Dresden, Germany
| | - M Sergon
- Institut of Pathology, Universitätsklinikum Carl Gustav Carus, TU Dresden, Dresden, Germany
| | - J Pablik
- Institut of Pathology, Universitätsklinikum Carl Gustav Carus, TU Dresden, Dresden, Germany
| | - S Abraham
- Department of Dermatology, Universitätsklinikum Carl Gustav Carus, TU Dresden, Dresden, Germany
| | - C M Hedrich
- Department of Women's & Children's Health, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom; Department of Paediatric Rheumatology, Alder Hey Children's NHS Foundation Trust Hospital, Liverpool, United Kingdom.
| |
Collapse
|
|
8
|
Dutta S, Mudaranthakam DP, Li Y, Sardiu ME. PerSEveML: a web-based tool to identify persistent biomarker structure for rare events using an integrative machine learning approach. Mol Omics 2024; 20:348-358. [PMID: 38690925 DOI: 10.1039/d4mo00008k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/03/2024]
Abstract
Omics data sets often pose a computational challenge due to their high dimensionality, large size, and non-linear structures. Analyzing these data sets becomes especially daunting in the presence of rare events. Machine learning (ML) methods have gained traction for analyzing rare events, yet there has been limited exploration of bioinformatics tools that integrate ML techniques to comprehend the underlying biology. Expanding upon our previously developed computational framework of an integrative machine learning approach, we introduce PerSEveML, an interactive web-based tool that uses crowd-sourced intelligence to predict rare events and determine feature selection structures. PerSEveML provides a comprehensive overview of the integrative approach through evaluation metrics that help users understand the contribution of individual ML methods to the prediction process. Additionally, PerSEveML calculates entropy and rank scores, which visually organize input features into a persistent structure of selected, unselected, and fluctuating categories that help researchers uncover meaningful hypotheses regarding the underlying biology. We have evaluated PerSEveML on three diverse biologically complex data sets with extremely rare events from small to large scale and have demonstrated its ability to generate valid hypotheses. PerSEveML is available at https://biostats-shinyr.kumc.edu/PerSEveML/ and https://github.com/sreejatadutta/PerSEveML.
Collapse
Affiliation(s)
- Sreejata Dutta
- Department of Biostatistics & Data Science, University of Kansas Medical Center, Kansas City, Kansas, USA.
| | - Dinesh Pal Mudaranthakam
- Department of Biostatistics & Data Science, University of Kansas Medical Center, Kansas City, Kansas, USA.
- University of Kansas Cancer Center, Kansas City, USA
| | - Yanming Li
- Department of Biostatistics & Data Science, University of Kansas Medical Center, Kansas City, Kansas, USA.
- University of Kansas Cancer Center, Kansas City, USA
| | - Mihaela E Sardiu
- Department of Biostatistics & Data Science, University of Kansas Medical Center, Kansas City, Kansas, USA.
- University of Kansas Cancer Center, Kansas City, USA
- Kansas Institute for Precision Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA
| |
Collapse
|
|
9
|
Chen S, Liang B, Xu J. Unveiling heterogeneity in MSCs: exploring marker-based strategies for defining MSC subpopulations. J Transl Med 2024; 22:459. [PMID: 38750573 PMCID: PMC11094970 DOI: 10.1186/s12967-024-05294-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 05/11/2024] [Indexed: 05/19/2024] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) represent a heterogeneous cell population distributed throughout various tissues, demonstrating remarkable adaptability to microenvironmental cues and holding immense promise for disease treatment. However, the inherent diversity within MSCs often leads to variability in therapeutic outcomes, posing challenges for clinical applications. To address this heterogeneity, purification of MSC subpopulations through marker-based isolation has emerged as a promising approach to ensure consistent therapeutic efficacy. In this review, we discussed the reported markers of MSCs, encompassing those developed through candidate marker strategies and high-throughput approaches, with the aim of explore viable strategies for addressing the heterogeneity of MSCs and illuminate prospective research directions in this field.
Collapse
Affiliation(s)
- Si Chen
- Shenzhen University Medical School, Shenzhen University, Shenzhen, 518000, People's Republic of China
| | - Bowei Liang
- Shenzhen University Medical School, Shenzhen University, Shenzhen, 518000, People's Republic of China
| | - Jianyong Xu
- Shenzhen Key Laboratory of Reproductive Immunology for Peri-Implantation, Guangdong Engineering Technology Research Center of Reproductive Immunology for Peri-Implantation, Shenzhen Zhongshan Obstetrics & Gynecology Hospital (formerly Shenzhen Zhongshan Urology Hospital), Fuqiang Avenue 1001, Shenzhen, 518060, Guangdong, People's Republic of China.
- Guangdong Engineering Technology Research Center of Reproductive Immunology for Peri-Implantation, Shenzhen, 518000, People's Republic of China.
| |
Collapse
|
|
10
|
Kabore MD, McElrath CC, Ali MAE, Almengo K, Gangaplara A, Fisher C, Barreto MA, Shaikh A, Olkhanud PB, Xu X, Gaskin D, Lopez-Ocasio M, Saxena A, McCoy JP, Fitzhugh CD. Low dose post-transplant cyclophosphamide and sirolimus induce mixed chimerism with CTLA4-Ig or lymphocyte depletion in an MHC-mismatched murine allotransplantation model. Bone Marrow Transplant 2024; 59:615-624. [PMID: 38347187 PMCID: PMC11073977 DOI: 10.1038/s41409-024-02237-y] [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: 07/24/2023] [Revised: 01/26/2024] [Accepted: 01/31/2024] [Indexed: 02/18/2024]
Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) offers a curative option for patients with certain non-malignant hematological diseases. High-dose post-transplant cyclophosphamide (PT-Cy) (200 mg/kg) and sirolimus (3 mg/kg), (HiC) synergistically induce stable mixed chimerism. Further, sirolimus and cytotoxic T lymphocyte-associated antigen-4 immunoglobulin (CTLA4-Ig), also known as Abatacept (Aba), promote immune tolerance and allograft survival. Here, in a major histocompatibility complex (MHC)-mismatched allo-HCT murine model, we combined Aba and/or T-cell depleting anti-Thy1.2 (Thy) with a lower dose of PT-Cy (50 mg/kg) and Sirolimus (3 mg/kg), (LoC). While mice in the LoC group showed graft rejection, the addition of Thy to LoC induced similar donor chimerism levels when compared to the HiC group. However, the addition of Aba to LoC led to graft acceptance only in younger mice. When Thy was added to the LoC+Aba setting, graft acceptance was restored in both age groups. Engrafted groups displayed significantly reduced frequencies of recipient-specific interferon-γ-producing T cells as well as an increased frequency in regulatory T cells (Tregs) except in the LoC+Aba group. Splenocytes from engrafted mice showed no proliferation upon restimulation with Balb/c stimulators. Collectively, in combination with Aba or Thy, LoC may be considered to reduce graft rejection in patients who undergo allo-HCT.
Collapse
Affiliation(s)
- Mariama D Kabore
- Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Corbin C McElrath
- Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Mohamed A E Ali
- Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Katherine Almengo
- Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Arunakumar Gangaplara
- Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA
- Miltenyi Biotec, Gaithersburg, MD, 20878, USA
| | - Cameron Fisher
- Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Mauricio A Barreto
- Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Ahmad Shaikh
- Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - Purevdorj B Olkhanud
- Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Xin Xu
- Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Deanna Gaskin
- Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Maria Lopez-Ocasio
- Flow Cytometry Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Ankit Saxena
- Flow Cytometry Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - J Philip McCoy
- Flow Cytometry Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Courtney D Fitzhugh
- Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
| |
Collapse
|
|
11
|
Jinsheng L, Qing D, Junhao C, Qiqi S, Jieru C, Liwen Y, Zhiyun G, Tailin G, Jie W. Micro/nano topological modification of TiO 2 nanotubes activates Thy-1 signaling to control osteogenic differentiation of stem cells. SLAS DISCOVERY : ADVANCING LIFE SCIENCES R & D 2024; 29:100139. [PMID: 38169172 DOI: 10.1016/j.slasd.2023.12.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 12/04/2023] [Accepted: 12/30/2023] [Indexed: 01/05/2024]
Abstract
Micro/nano topological modification is critical for improving the in vivo behaviors of bone implants, regulating multiple cellular functions. Titania (TiO2) nanotubes show the capacity of promoting osteoblast-related cell differentiation and induce effective osseointegration, serving as a model material for studying the effects of micro/nano-topological modifications on cells. However, the intracellular signaling pathways by which TiO2 nanotubes regulate the osteogenic differentiation of stem cells are not fully defined. Thy-1 (CD90), a cell surface glycoprotein anchored by glycosylphosphatidylinositol, has been considered a key molecule in osteoblast differentiation in recent years. Nevertheless, whether the micro/nano topology of the implant surface leads to changes in Thy-1 is unknown, as well as whether these changes promote osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Here, TiO2 nanotubes of various diameters were prepared by adjusting the anodizing voltage. qPCR and immunoblot were carried out to assess the mechanism by which TiO2 nanotubes regulate Thy-1. The results revealed Ti plates harboring TiO2 nanotubes ∼100-nm diameter (TNT-100) markedly upregulated Thy-1. Subsequently, upregulated Thy-1 promoted the activation of Fyn/RhoA/MLC Ⅱ/F-actin axis, which enhanced the nuclear translocation of YAP. After Thy-1 knockdown by siRNA, the Fyn/RhoA/MLC Ⅱ/F-actin axis was significantly inhibited and TiO2 nanotubes showed decreased effects on osteogenic differentiation. Therefore, Thy-1 upregulation might be a major mechanism by which micro/nano-topological modification of TiO2 nanotubes promotes osteogenic differentiation in BMSCs. This study provides novel insights into the molecular mechanism of TiO2 nanotubes, which may help design improved bone implants for clinical application.
Collapse
Affiliation(s)
- Li Jinsheng
- Institute of Biomedical Engineering, College of Medicine, Southwest Jiaotong University, Chengdu 610031, Sichuan, China; Key Laboratory of Advanced Technologies of Materials Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, PR China
| | - Deng Qing
- Institute of Biomedical Engineering, College of Medicine, Southwest Jiaotong University, Chengdu 610031, Sichuan, China
| | - Chen Junhao
- School of Finance and Economics, Xizang Minzu University, Xianyang 712082, PR China
| | - Si Qiqi
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
| | - Chen Jieru
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
| | - Yang Liwen
- Institute of Biomedical Engineering, College of Medicine, Southwest Jiaotong University, Chengdu 610031, Sichuan, China; Key Laboratory of Advanced Technologies of Materials Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, PR China
| | - Guo Zhiyun
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
| | - Guo Tailin
- Institute of Biomedical Engineering, College of Medicine, Southwest Jiaotong University, Chengdu 610031, Sichuan, China; Key Laboratory of Advanced Technologies of Materials Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, PR China.
| | - Weng Jie
- Institute of Biomedical Engineering, College of Medicine, Southwest Jiaotong University, Chengdu 610031, Sichuan, China; Key Laboratory of Advanced Technologies of Materials Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, PR China.
| |
Collapse
|
|
12
|
Kunitake K, Motohashi N, Inoue T, Suzuki Y, Aoki Y. Characterization of CD90/Thy-1 as a crucial molecular signature for myogenic differentiation in human urine-derived cells through single-cell RNA sequencing. Sci Rep 2024; 14:2329. [PMID: 38282008 PMCID: PMC10822841 DOI: 10.1038/s41598-024-52530-5] [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: 06/16/2023] [Accepted: 01/19/2024] [Indexed: 01/30/2024] Open
Abstract
Human urine-derived cells (UDCs) are primary cultured cells originating from the upper urinary tract and are known to be multipotent. We previously developed MYOD1-transduced UDCs (MYOD1-UDCs) as a model recapitulating the pathogenesis of Duchenne muscular dystrophy (DMD) caused by a lack of dystrophin. MYOD1-UDCs also allow evaluation of the efficacy of exon skipping with antisense oligonucleotides. However, despite the introduction of MYOD1, some MYOD1-UDCs failed to form myotubes, possibly because of heterogeneity among UDCs. Here, we carried out single-cell RNA-sequencing analyses and revealed that CD90/Thy-1 was highly expressed in a limited subpopulation of UDCs with high myogenic potency. Furthermore, CD90-positive MYOD1-UDCs, but not CD90-negative cells, could form myotubes expressing high levels of myosin heavy chain and dystrophin. Notably, overexpression of CD90 in CD90-negative MYOD1-UDCs did not enhance myogenic differentiation, whereas CD90 suppression in CD90-positive UDCs led to decreased myotube formation and decreased myosin heavy chain expression. CD90 may thus contribute to the fusion of single-nucleated MYOD1-UDCs into myotubes but is not crucial for promoting the expression of late muscle regulatory factors. Finally, we confirmed that CD90-positive MYOD1-UDCs derived from patients with DMD were a valuable tool for obtaining a highly reproducible and stable evaluation of exon skipping using antisense oligonucleotide.
Collapse
Affiliation(s)
- Katsuhiko Kunitake
- Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawa-Higashi, Kodaira, Tokyo, 187-8502, Japan
- Department of NCNP Brain Physiology and Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Norio Motohashi
- Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawa-Higashi, Kodaira, Tokyo, 187-8502, Japan
| | - Takafumi Inoue
- Department of Life Science and Medical Bioscience, Waseda University, Tokyo, Japan
| | - Yutaka Suzuki
- Laboratory of Systems Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
| | - Yoshitsugu Aoki
- Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawa-Higashi, Kodaira, Tokyo, 187-8502, Japan.
- Department of NCNP Brain Physiology and Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
| |
Collapse
|
|
13
|
Tawfeeq C, Song J, Khaniya U, Madej T, Wang J, Youkharibache P, Abrol R. Towards a structural and functional analysis of the immunoglobulin-fold proteome. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2024; 138:135-178. [PMID: 38220423 DOI: 10.1016/bs.apcsb.2023.11.002] [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: 01/16/2024]
Abstract
The immunoglobulin fold (Ig fold) domain is a super-secondary structural motif consisting of a sandwich with two layers of β-sheets that is present in many proteins with very diverse biological functions covering a wide range of physiological processes. This domain presents a modular architecture built with β strands connected by variable length loops that has a highly conserved structural core of four β-strands and quite variable β-sheet extensions in the two sandwich layers that enable both divergent and convergent evolutionary mechanisms in the known Ig fold proteome. The central role of this Ig fold's structural plasticity in the evolutionary success of antibodies in our immune system is well established. Nature has also utilized this Ig fold in all domains of life in many different physiological contexts that go way beyond the immune system. Here we will present a structural and functional overview of the utilization of the Ig fold in different biological processes and in different cellular contexts to highlight some of the innumerable ways that this structural motif can interact in multidomain proteins to enable their diversity of functions. This includes shareable specific protein structure visualizations behind those functions that serve as starting points for further explorations of the biomolecular interactions spanning the Ig fold proteome. This overview also highlights how this Ig fold is being utilized through natural adaptation, engineering, and even building from scratch for a range of biotechnological applications.
Collapse
Affiliation(s)
- Caesar Tawfeeq
- Department of Chemistry and Biochemistry, California State University Northridge, Northridge, United States
| | - James Song
- National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, United States
| | - Umesh Khaniya
- Cancer Data Science Laboratory, National Cancer Institute, National Institutes of Health, Bethesda, United States
| | - Thomas Madej
- National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, United States
| | - Jiyao Wang
- National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, United States
| | - Philippe Youkharibache
- Cancer Data Science Laboratory, National Cancer Institute, National Institutes of Health, Bethesda, United States.
| | - Ravinder Abrol
- Department of Chemistry and Biochemistry, California State University Northridge, Northridge, United States.
| |
Collapse
|
|
14
|
Sukowati CH, El-Khobar K, Jasirwan COM, Kurniawan J, Gani RA. Stemness markers in hepatocellular carcinoma of Eastern vs. Western population: Etiology matters? Ann Hepatol 2024; 29:101153. [PMID: 37734662 DOI: 10.1016/j.aohep.2023.101153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Accepted: 08/22/2023] [Indexed: 09/23/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers with a high mortality rate. HCC development is associated with its underlying etiologies, mostly caused by infection of chronic hepatitis B virus (HBV) and hepatitis C virus (HCV), alcohol, non-alcoholic fatty liver disease, and exposure to aflatoxins. These variables, together with human genetic susceptibility, contribute to HCC molecular heterogeneity, including at the cellular level. HCC initiation, tumor recurrence, and drug resistance rates have been attributed to the presence of liver cancer stem cells (CSC). This review summarizes available data regarding whether various HCC etiologies may be associated to the appearance of CSC biomarkers. It also described the genetic variations of tumoral tissues obtained from Western and Eastern populations, in particular to the oncogenic effect of HBV in the human genome.
Collapse
Affiliation(s)
- Caecilia Hc Sukowati
- Liver Cancer Unit, Fondazione Italiana Fegato ONLUS, AREA Science Park campus Basovizza, SS14 km 163.5, Trieste 34149, Italy; Eijkman Research Center for Molecular Biology, National Research and Innovation Agency of Indonesia (BRIN), B.J. Habibie Building, Jl. M.H. Thamrin No. 8, Jakarta Pusat 10340, Indonesia.
| | - Korri El-Khobar
- Eijkman Research Center for Molecular Biology, National Research and Innovation Agency of Indonesia (BRIN), B.J. Habibie Building, Jl. M.H. Thamrin No. 8, Jakarta Pusat 10340, Indonesia
| | - Chyntia Olivia Maurine Jasirwan
- Hepatobiliary Division, Medical Staff Group of Internal Medicine, Faculty of Medicine, Universitas Indonesia - Dr. Cipto Mangunkusumo General Hospital, Jl. Pangeran Diponegoro No.71, Jakarta 10430, Indonesia
| | - Juferdy Kurniawan
- Hepatobiliary Division, Medical Staff Group of Internal Medicine, Faculty of Medicine, Universitas Indonesia - Dr. Cipto Mangunkusumo General Hospital, Jl. Pangeran Diponegoro No.71, Jakarta 10430, Indonesia
| | - Rino Alvani Gani
- Hepatobiliary Division, Medical Staff Group of Internal Medicine, Faculty of Medicine, Universitas Indonesia - Dr. Cipto Mangunkusumo General Hospital, Jl. Pangeran Diponegoro No.71, Jakarta 10430, Indonesia
| |
Collapse
|
|
15
|
Valdivia A, Avalos AM, Leyton L. Thy-1 (CD90)-regulated cell adhesion and migration of mesenchymal cells: insights into adhesomes, mechanical forces, and signaling pathways. Front Cell Dev Biol 2023; 11:1221306. [PMID: 38099295 PMCID: PMC10720913 DOI: 10.3389/fcell.2023.1221306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Accepted: 09/25/2023] [Indexed: 12/17/2023] Open
Abstract
Cell adhesion and migration depend on the assembly and disassembly of adhesive structures known as focal adhesions. Cells adhere to the extracellular matrix (ECM) and form these structures via receptors, such as integrins and syndecans, which initiate signal transduction pathways that bridge the ECM to the cytoskeleton, thus governing adhesion and migration processes. Integrins bind to the ECM and soluble or cell surface ligands to form integrin adhesion complexes (IAC), whose composition depends on the cellular context and cell type. Proteomic analyses of these IACs led to the curation of the term adhesome, which is a complex molecular network containing hundreds of proteins involved in signaling, adhesion, and cell movement. One of the hallmarks of these IACs is to sense mechanical cues that arise due to ECM rigidity, as well as the tension exerted by cell-cell interactions, and transduce this force by modifying the actin cytoskeleton to regulate cell migration. Among the integrin/syndecan cell surface ligands, we have described Thy-1 (CD90), a GPI-anchored protein that possesses binding domains for each of these receptors and, upon engaging them, stimulates cell adhesion and migration. In this review, we examine what is currently known about adhesomes, revise how mechanical forces have changed our view on the regulation of cell migration, and, in this context, discuss how we have contributed to the understanding of signaling mechanisms that control cell adhesion and migration.
Collapse
Affiliation(s)
- Alejandra Valdivia
- Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA, United States
| | - Ana María Avalos
- Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Santiago, Chile
| | - Lisette Leyton
- Cellular Communication Laboratory, Programa de Biología Celular y Molecular, Center for Studies on Exercise, Metabolism and Cancer (CEMC), Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago, Chile
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences & Faculty of Medicine, Universidad de Chile, Santiago, Chile
| |
Collapse
|
|
16
|
Ravn-Boess N, Roy N, Hattori T, Bready D, Donaldson H, Lawson C, Lapierre C, Korman A, Rodrick T, Liu E, Frenster JD, Stephan G, Wilcox J, Corrado AD, Cai J, Ronnen R, Wang S, Haddock S, Sabio Ortiz J, Mishkit O, Khodadadi-Jamayran A, Tsirigos A, Fenyö D, Zagzag D, Drube J, Hoffmann C, Perna F, Jones DR, Possemato R, Koide A, Koide S, Park CY, Placantonakis DG. The expression profile and tumorigenic mechanisms of CD97 (ADGRE5) in glioblastoma render it a targetable vulnerability. Cell Rep 2023; 42:113374. [PMID: 37938973 PMCID: PMC10841603 DOI: 10.1016/j.celrep.2023.113374] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 09/08/2023] [Accepted: 10/19/2023] [Indexed: 11/10/2023] Open
Abstract
Glioblastoma (GBM) is the most common and aggressive primary brain malignancy. Adhesion G protein-coupled receptors (aGPCRs) have attracted interest for their potential as treatment targets. Here, we show that CD97 (ADGRE5) is the most promising aGPCR target in GBM, by virtue of its de novo expression compared to healthy brain tissue. CD97 knockdown or knockout significantly reduces the tumor initiation capacity of patient-derived GBM cultures (PDGCs) in vitro and in vivo. We find that CD97 promotes glycolytic metabolism via the mitogen-activated protein kinase (MAPK) pathway, which depends on phosphorylation of its C terminus and recruitment of β-arrestin. We also demonstrate that THY1/CD90 is a likely CD97 ligand in GBM. Lastly, we show that an anti-CD97 antibody-drug conjugate selectively kills tumor cells in vitro. Our studies identify CD97 as a regulator of tumor metabolism, elucidate mechanisms of receptor activation and signaling, and provide strong scientific rationale for developing biologics to target it therapeutically in GBM.
Collapse
Affiliation(s)
- Niklas Ravn-Boess
- Department of Neurosurgery, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Nainita Roy
- Department of Pathology, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Takamitsu Hattori
- Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY 10016, USA; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Devin Bready
- Department of Neurosurgery, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Hayley Donaldson
- Department of Neurosurgery, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Christopher Lawson
- Department of Neurosurgery, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Cathryn Lapierre
- Department of Neurosurgery, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Aryeh Korman
- Metabolomics Laboratory, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Tori Rodrick
- Metabolomics Laboratory, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Enze Liu
- Department of Medicine, Division of Hematology/Oncology, Indiana University, Indianapolis, IN 46202, USA
| | - Joshua D Frenster
- Department of Neurosurgery, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Gabriele Stephan
- Department of Neurosurgery, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Jordan Wilcox
- Department of Neurosurgery, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Alexis D Corrado
- Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY 10016, USA; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Julia Cai
- Department of Neurosurgery, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Rebecca Ronnen
- Department of Neurosurgery, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Shuai Wang
- Department of Neurosurgery, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Sara Haddock
- Department of Neurosurgery, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Jonathan Sabio Ortiz
- Department of Neurosurgery, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Orin Mishkit
- Preclinical Imaging Laboratory, NYU Grossman School of Medicine, New York, NY 10016, USA
| | | | - Aris Tsirigos
- Applied Bioinformatics Laboratories, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - David Fenyö
- Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA; Institute for Systems Genetics, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - David Zagzag
- Department of Neurosurgery, NYU Grossman School of Medicine, New York, NY 10016, USA; Department of Pathology, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Julia Drube
- Institute for Molecular Cell Biology, Universitätsklinikum Jena, 07745 Jena, Germany
| | - Carsten Hoffmann
- Institute for Molecular Cell Biology, Universitätsklinikum Jena, 07745 Jena, Germany
| | | | - Drew R Jones
- Metabolomics Laboratory, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Richard Possemato
- Department of Pathology, NYU Grossman School of Medicine, New York, NY 10016, USA; Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Akiko Koide
- Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY 10016, USA; Department of Medicine, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Shohei Koide
- Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY 10016, USA; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Christopher Y Park
- Department of Pathology, NYU Grossman School of Medicine, New York, NY 10016, USA; Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Dimitris G Placantonakis
- Department of Neurosurgery, NYU Grossman School of Medicine, New York, NY 10016, USA; Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY 10016, USA; Kimmel Center for Stem Cell Biology, NYU Grossman School of Medicine, New York, NY 10016, USA; Brain and Spine Tumor Center, NYU Grossman School of Medicine, New York, NY 10016, USA; Neuroscience Institute, NYU Grossman School of Medicine, New York, NY 10016, USA.
| |
Collapse
|
|
17
|
Dutta S, Box AC, Li Y, Sardiu ME. Identifying dynamical persistent biomarker structures for rare events using modern integrative machine learning approach. Proteomics 2023; 23:e2200290. [PMID: 36852539 PMCID: PMC11503472 DOI: 10.1002/pmic.202200290] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 01/30/2023] [Accepted: 02/17/2023] [Indexed: 03/01/2023]
Abstract
The evolution of omics and computational competency has accelerated discoveries of the underlying biological processes in an unprecedented way. High throughput methodologies, such as flow cytometry, can reveal deeper insights into cell processes, thereby allowing opportunities for scientific discoveries related to health and diseases. However, working with cytometry data often imposes complex computational challenges due to high-dimensionality, large size, and nonlinearity of the data structure. In addition, cytometry data frequently exhibit diverse patterns across biomarkers and suffer from substantial class imbalances which can further complicate the problem. The existing methods of cytometry data analysis either predict cell population or perform feature selection. Through this study, we propose a "wisdom of the crowd" approach to simultaneously predict rare cell populations and perform feature selection by integrating a pool of modern machine learning (ML) algorithms. Given that our approach integrates superior performing ML models across different normalization techniques based on entropy and rank, our method can detect diverse patterns existing across the model features. Furthermore, the method identifies a dynamic biomarker structure that divides the features into persistently selected, unselected, and fluctuating assemblies indicating the role of each biomarker in rare cell prediction, which can subsequently aid in studies of disease progression.
Collapse
Affiliation(s)
- Sreejata Dutta
- Department of Biostatistics & Data Science, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Andrew C. Box
- Stowers Institute for Medical Research, Kansas City, Missouri, USA
| | - Yanming Li
- Department of Biostatistics & Data Science, University of Kansas Medical Center, Kansas City, Kansas, USA
- University of Kansas Cancer Center, Kansas City, Kansas, USA
| | - Mihaela E. Sardiu
- Department of Biostatistics & Data Science, University of Kansas Medical Center, Kansas City, Kansas, USA
- University of Kansas Cancer Center, Kansas City, Kansas, USA
- Kansas Institute for Precision Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA
| |
Collapse
|
|
18
|
Zhou Z, Zhang H, Tao Y, Zang J, Zhao J, Li H, Wang Y, Wang T, Zhao H, Wang F, Guo C, Zhu F, Mao H, Liu F, Zhang L, Wang Q. FGF21 alleviates adipose stem cell senescence via CD90 glycosylation-dependent glucose influx in remodeling healthy white adipose tissue. Redox Biol 2023; 67:102877. [PMID: 37690164 PMCID: PMC10497791 DOI: 10.1016/j.redox.2023.102877] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 09/04/2023] [Accepted: 09/04/2023] [Indexed: 09/12/2023] Open
Abstract
The senescence of adipose stem cells (ASCs) impairs healthy adipose tissue remodeling, causing metabolic maladaptation to energy surplus. The intrinsic molecular pathways and potential therapy targets for ASC senescence are largely unclear. Here, we showed that visceral ASCs were prone to senescence that was caused by reactive oxygen species (ROS) overload, especially mitochondrial ROS. These senescent ASCs failed to sustain efficient glucose influx, pentose phosphate pathway (PPP) and redox homeostasis. We showed that CD90 silence restricted the glucose uptake by ASCs and thus disrupted their PPP and anti-oxidant system, resulting in ASC senescence. Notably, fibroblast growth factor 21 (FGF21) treatment significantly reduced the senescent phenotypes of ASCs by augmenting CD90 protein via glycosylation, which promoted glucose influx via the AKT-GLUT4 axis and therefore mitigated ROS overload. For diet-induced obese mice, chronic administration of low-dose FGF21 relieved their visceral white adipose tissue (VAT) dysfunction and systemic metabolic disorders. In particular, VAT homeostasis was restored in FGF21-treated obese mice, where ASC repertoire was markedly recovered, accompanied by CD90 elevation and anti-senescent phenotypes in these ASCs. Collectively, we reveal a molecular mechanism of ASC senescence by which CD90 downregulation interferes glucose influx into PPP and redox homeostasis. And we propose a FGF21-based strategy for healthy VAT remodeling, which targets CD90 glycosylation to correct ASC senescence and therefore combat obesity-related metabolic dysfunction.
Collapse
Affiliation(s)
- Zixin Zhou
- Key Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Huiying Zhang
- Key Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Yan Tao
- Key Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Jinhao Zang
- Key Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Jingyuan Zhao
- Key Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Huijie Li
- Key Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Yalin Wang
- Key Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Tianci Wang
- Key Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Hui Zhao
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250033, China
| | - Fuwu Wang
- Key Laboratory for Experimental Teratology of Ministry of Education, Shandong Key Laboratory of Mental Disorders, Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Chun Guo
- Key Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Faliang Zhu
- Key Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Haiting Mao
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250033, China
| | - Fengming Liu
- Key Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Lining Zhang
- Key Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Qun Wang
- Key Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China.
| |
Collapse
|
|
19
|
Dutta S, Mudaranthakam DP, Li Y, Sardiu ME. PerSEveML: A Web-Based Tool to Identify Persistent Biomarker Structure for Rare Events Using Integrative Machine Learning Approach. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.10.25.564000. [PMID: 38196661 PMCID: PMC10775315 DOI: 10.1101/2023.10.25.564000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2024]
Abstract
Omics datasets often pose a computational challenge due to their high dimensionality, large size, and non-linear structures. Analyzing these datasets becomes especially daunting in the presence of rare events. Machine learning (ML) methods have gained traction for analyzing rare events, yet there remains a limited exploration of bioinformatics tools that integrate ML techniques to comprehend the underlying biology. Expanding upon our previously developed computational framework of an integrative machine learning approach1, we introduce PerSEveML, an interactive web-based that uses crowd-sourced intelligence to predict rare events and determine feature selection structures. PerSEveML provides a comprehensive overview of the integrative approach through evaluation metrics that help users understand the contribution of individual ML methods to the prediction process. Additionally, PerSEveML calculates entropy and rank scores, which visually organize input features into a persistent structure of selected, unselected, and fluctuating categories that help researchers uncover meaningful hypotheses regarding the underlying biology. We have evaluated PerSEveML on three diverse biologically complex data sets with extremely rare events from small to large scale and have demonstrated its ability to generate valid hypotheses. PerSEveML is available at https://biostats-shinyr.kumc.edu/PerSEveML/ and https://github.com/sreejatadutta/PerSEveML.
Collapse
Affiliation(s)
- Sreejata Dutta
- Department of Biostatistics & Data Science, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Dinesh Pal Mudaranthakam
- Department of Biostatistics & Data Science, University of Kansas Medical Center, Kansas City, Kansas, USA
- University of Kansas Cancer Center, Kansas City, USA
| | - Yanming Li
- Department of Biostatistics & Data Science, University of Kansas Medical Center, Kansas City, Kansas, USA
- University of Kansas Cancer Center, Kansas City, USA
| | - Mihaela E Sardiu
- Department of Biostatistics & Data Science, University of Kansas Medical Center, Kansas City, Kansas, USA
- University of Kansas Cancer Center, Kansas City, USA
- Kansas Institute for Precision Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA
| |
Collapse
|
|
20
|
Koprivica I, Stanisavljević S, Mićanović D, Jevtić B, Stojanović I, Miljković Đ. ILC3: a case of conflicted identity. Front Immunol 2023; 14:1271699. [PMID: 37915588 PMCID: PMC10616800 DOI: 10.3389/fimmu.2023.1271699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Accepted: 10/02/2023] [Indexed: 11/03/2023] Open
Abstract
Innate lymphoid cells type 3 (ILC3s) are the first line sentinels at the mucous tissues, where they contribute to the homeostatic immune response in a major way. Also, they have been increasingly appreciated as important modulators of chronic inflammatory and autoimmune responses, both locally and systemically. The proper identification of ILC3 is of utmost importance for meaningful studies on their role in immunity. Flow cytometry is the method of choice for the detection and characterization of ILC3. However, the analysis of ILC3-related papers shows inconsistency in ILC3 phenotypic definition, as different inclusion and exclusion markers are used for their identification. Here, we present these discrepancies in the phenotypic characterization of human and mouse ILC3s. We discuss the pros and cons of using various markers for ILC3 identification. Furthermore, we consider the possibilities for the efficient isolation and propagation of ILC3 from different organs and tissues for in-vitro and in-vivo studies. This paper calls upon uniformity in ILC3 definition, isolation, and propagation for the increased possibility of confluent interpretation of ILC3's role in immunity.
Collapse
Affiliation(s)
| | | | | | | | | | - Đorđe Miljković
- Department of Immunology, Institute for Biological Research “Siniša Stanković” - National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia
| |
Collapse
|
|
21
|
Iżycka N, Zaborowski MP, Ciecierski Ł, Jaz K, Szubert S, Miedziarek C, Rezler M, Piątek-Bajan K, Synakiewicz A, Jankowska A, Figlerowicz M, Sterzyńska K, Nowak-Markwitz E. Cancer Stem Cell Markers-Clinical Relevance and Prognostic Value in High-Grade Serous Ovarian Cancer (HGSOC) Based on The Cancer Genome Atlas Analysis. Int J Mol Sci 2023; 24:12746. [PMID: 37628927 PMCID: PMC10454196 DOI: 10.3390/ijms241612746] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 08/05/2023] [Accepted: 08/09/2023] [Indexed: 08/27/2023] Open
Abstract
Cancer stem cells (CSCs) may contribute to an increased risk of recurrence in ovarian cancer (OC). Further research is needed to identify associations between CSC markers and OC patients' clinical outcomes with greater certainty. If they prove to be correct, in the future, the CSC markers can be used to help predict survival and indicate new therapeutic targets. This study aimed to determine the CSC markers at mRNA and protein levels and their association with clinical presentation, outcome, and risk of recurrence in HGSOC (High-Grade Serous Ovarian Cancer). TCGA (The Cancer Genome Atlas) database with 558 ovarian cancer tumor samples was used for the evaluation of 13 CSC markers (ALDH1A1, CD44, EPCAM, KIT, LGR5, NES, NOTCH3, POU5F1, PROM1, PTTG1, ROR1, SOX9, and THY1). Data on mRNA and protein levels assessed by microarray and mass spectrometry were retrieved from TCGA. Models to predict chemotherapy response and survival were built using multiple variables, including epidemiological data, expression levels, and machine learning methodology. ALDH1A1 and LGR5 mRNA expressions indicated a higher platinum sensitivity (p = 3.50 × 10-3; p = 0.01, respectively). POU5F1 mRNA expression marked platinum-resistant tumors (p = 9.43 × 10-3). CD44 and EPCAM mRNA expression correlated with longer overall survival (OS) (p = 0.043; p = 0.039, respectively). THY1 mRNA and protein levels were associated with worse OS (p = 0.019; p = 0.015, respectively). Disease-free survival (DFS) was positively affected by EPCAM (p = 0.004), LGR5 (p = 0.018), and CD44 (p = 0.012). In the multivariate model based on CSC marker expression, the high-risk group had 9.1 months longer median overall survival than the low-risk group (p < 0.001). ALDH1A1, CD44, EPCAM, LGR5, POU5F1, and THY1 levels in OC may be used as prognostic factors for the primary outcome and help predict the treatment response.
Collapse
Affiliation(s)
- Natalia Iżycka
- Department of Gynecology, Obstetrics and Gynecologic Oncology, Division of Gynecologic Oncology, Poznan University of Medical Sciences, Polna 33 St., 60-535 Poznan, Poland (S.S.)
| | - Mikołaj Piotr Zaborowski
- Department of Gynecology, Obstetrics and Gynecologic Oncology, Division of Gynecologic Oncology, Poznan University of Medical Sciences, Polna 33 St., 60-535 Poznan, Poland (S.S.)
- European Center for Bioinformatics and Genomics, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704 Poznan, Poland (M.F.)
| | - Łukasz Ciecierski
- European Center for Bioinformatics and Genomics, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704 Poznan, Poland (M.F.)
| | - Kamila Jaz
- Department of Gynecology, Obstetrics and Gynecologic Oncology, Division of Gynecologic Oncology, Poznan University of Medical Sciences, Polna 33 St., 60-535 Poznan, Poland (S.S.)
| | - Sebastian Szubert
- Department of Gynecology, Obstetrics and Gynecologic Oncology, Division of Gynecologic Oncology, Poznan University of Medical Sciences, Polna 33 St., 60-535 Poznan, Poland (S.S.)
| | - Cezary Miedziarek
- Department of Gynecology, Obstetrics and Gynecologic Oncology, Division of Gynecologic Oncology, Poznan University of Medical Sciences, Polna 33 St., 60-535 Poznan, Poland (S.S.)
| | - Marta Rezler
- Department of Gynecology, Obstetrics and Gynecologic Oncology, Division of Gynecologic Oncology, Poznan University of Medical Sciences, Polna 33 St., 60-535 Poznan, Poland (S.S.)
| | - Kinga Piątek-Bajan
- Department of Gynecology, Obstetrics and Gynecologic Oncology, Division of Gynecologic Oncology, Poznan University of Medical Sciences, Polna 33 St., 60-535 Poznan, Poland (S.S.)
| | - Aneta Synakiewicz
- Department of Gynecology, Obstetrics and Gynecologic Oncology, Division of Gynecologic Oncology, Poznan University of Medical Sciences, Polna 33 St., 60-535 Poznan, Poland (S.S.)
| | - Anna Jankowska
- Department of Cell Biology, Poznan University of Medical Sciences, Rokietnicka 5D St., 60-806 Poznan, Poland;
| | - Marek Figlerowicz
- European Center for Bioinformatics and Genomics, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704 Poznan, Poland (M.F.)
| | - Karolina Sterzyńska
- Department of Histology and Embryology, Poznan University of Medical Sciences, Swiecickiego 6 St., 61-781 Poznan, Poland
| | - Ewa Nowak-Markwitz
- Department of Gynecology, Obstetrics and Gynecologic Oncology, Division of Gynecologic Oncology, Poznan University of Medical Sciences, Polna 33 St., 60-535 Poznan, Poland (S.S.)
| |
Collapse
|
|
22
|
Anjos-Afonso F, Bonnet D. Human CD34+ hematopoietic stem cell hierarchy: how far are we with its delineation at the most primitive level? Blood 2023; 142:509-518. [PMID: 37018661 PMCID: PMC10644061 DOI: 10.1182/blood.2022018071] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 03/17/2023] [Accepted: 03/19/2023] [Indexed: 04/07/2023] Open
Abstract
The ability to isolate and characterize different hematopoietic stem cell (HSC) or progenitor cell populations opens avenues to understand how hematopoiesis is regulated during development, homeostasis, and regeneration as well as in age-related conditions such as clonal hematopoiesis and leukemogenesis. Significant progress has been made in the past few decades in determining the composition of the cell types that exist in this system, but the most significant advances have come from mouse studies. However, recent breakthroughs have made significant strides that have enhanced the resolution of the human primitive hematopoietic compartment. Therefore, we aim to review this subject not only from a historical perspective but also to discuss the progress made in the characterization of the human postnatal CD34+ HSC-enriched populations. This approach will enable us to shed light on the potential future translational applicability of human HSCs.
Collapse
Affiliation(s)
- Fernando Anjos-Afonso
- Haematopoietic Signalling Group, European Cancer Stem Cell Institute, School of Biosciences, Cardiff University, Cardiff, United Kingdom
- Haematopoietic Stem Cell Laboratory, Francis Crick Institute, London, United Kingdom
| | - Dominique Bonnet
- Haematopoietic Stem Cell Laboratory, Francis Crick Institute, London, United Kingdom
| |
Collapse
|
|
23
|
Piwocka O, Musielak M, Piotrowski I, Kulcenty K, Adamczyk B, Fundowicz M, Suchorska WM, Malicki J. Primary cancer-associated fibroblasts exhibit high heterogeneity among breast cancer subtypes. Rep Pract Oncol Radiother 2023; 28:159-171. [PMID: 37456709 PMCID: PMC10348329 DOI: 10.5603/rpor.a2023.0026] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 05/02/2023] [Indexed: 07/18/2023] Open
Abstract
Background Cancer-associated fibroblasts (CAFs) are a diverse subset of cells, that is recently gaining in popularity and have the potential to become a new target for breast cancer (BC) therapy; however, broader research is required to understand their mechanisms and interactions with breast cancer cells. The goal of the study was to isolate CAFs from breast cancer tumour and characterise isolated cell lines. We concentrated on numerous CAF biomarkers that would enable their differentiation. Materials and methods Flow cytometry, immunofluorescence, and reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) were used to phenotype the primary CAFs. Results/Conclusions According to our findings, there was no significant pattern in the classification of cancer-associated fibroblasts. The results of biomarkers expression were heterogeneous, thus no specific subtypes were identified. Furthermore, a comparison of cancer-associated fibroblasts derived from different BC subtypes (luminal A and B, triple-negative, HER2 positive) did not reveal any clear trend of expression.
Collapse
Affiliation(s)
- Oliwia Piwocka
- Radiobiology Laboratory, Department of Medical Physics, Greater Poland Cancer Centre, Poznań, Poland
- Department of Electroradiology, Poznan University of Medical Sciences, Poznań, Poland
- Doctoral School, Poznan University of Medical Sciences, Poznań, Poland
| | - Marika Musielak
- Radiobiology Laboratory, Department of Medical Physics, Greater Poland Cancer Centre, Poznań, Poland
- Department of Electroradiology, Poznan University of Medical Sciences, Poznań, Poland
- Doctoral School, Poznan University of Medical Sciences, Poznań, Poland
| | - Igor Piotrowski
- Radiobiology Laboratory, Department of Medical Physics, Greater Poland Cancer Centre, Poznań, Poland
| | - Katarzyna Kulcenty
- Radiobiology Laboratory, Department of Medical Physics, Greater Poland Cancer Centre, Poznań, Poland
| | - Beata Adamczyk
- Breast Surgical Oncology Department, Greater Poland Cancer Centre, Poznań, Poland
| | | | - Wiktoria Maria Suchorska
- Radiobiology Laboratory, Department of Medical Physics, Greater Poland Cancer Centre, Poznań, Poland
- Department of Electroradiology, Poznan University of Medical Sciences, Poznań, Poland
| | - Julian Malicki
- Department of Electroradiology, Poznan University of Medical Sciences, Poznań, Poland
- Medical Physics Department, Greater Poland Cancer Centre, Poznań, Poland
| |
Collapse
|
|
24
|
Canale FP, Neumann J, von Renesse J, Loggi E, Pecoraro M, Vogel I, Zoppi G, Antonini G, Wolf T, Jin W, Zheng X, La Barba G, Birgin E, Forkel M, Nilsson T, Marone R, Mueller H, Pelletier N, Jeker LT, Civenni G, Schlapbach C, Catapano CV, Seifert L, Seifert AM, Gillessen S, De Dosso S, Cristaudi A, Rahbari NN, Ercolani G, Geiger R. Proteomics of immune cells from liver tumors reveals immunotherapy targets. CELL GENOMICS 2023; 3:100331. [PMID: 37388918 PMCID: PMC10300607 DOI: 10.1016/j.xgen.2023.100331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 03/13/2023] [Accepted: 05/02/2023] [Indexed: 07/01/2023]
Abstract
Elucidating the mechanisms by which immune cells become dysfunctional in tumors is critical to developing next-generation immunotherapies. We profiled proteomes of cancer tissue as well as monocyte/macrophages, CD4+ and CD8+ T cells, and NK cells isolated from tumors, liver, and blood of 48 patients with hepatocellular carcinoma. We found that tumor macrophages induce the sphingosine-1-phospate-degrading enzyme SGPL1, which dampened their inflammatory phenotype and anti-tumor function in vivo. We further discovered that the signaling scaffold protein AFAP1L2, typically only found in activated NK cells, is also upregulated in chronically stimulated CD8+ T cells in tumors. Ablation of AFAP1L2 in CD8+ T cells increased their viability upon repeated stimulation and enhanced their anti-tumor activity synergistically with PD-L1 blockade in mouse models. Our data reveal new targets for immunotherapy and provide a resource on immune cell proteomes in liver cancer.
Collapse
Affiliation(s)
- Fernando P. Canale
- Institute for Research in Biomedicine (IRB), Bellinzona, Switzerland
- Università della Svizzera italiana (USI), Lugano, Switzerland
| | - Julia Neumann
- Institute for Research in Biomedicine (IRB), Bellinzona, Switzerland
- Università della Svizzera italiana (USI), Lugano, Switzerland
| | - Janusz von Renesse
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- National Center for Tumor Diseases (NCT), Dresden, Germany
| | - Elisabetta Loggi
- Hepatology Unit, Department of Medical & Surgical Sciences, University of Bologna, Bologna, Italy
| | - Matteo Pecoraro
- Institute for Research in Biomedicine (IRB), Bellinzona, Switzerland
- Università della Svizzera italiana (USI), Lugano, Switzerland
| | - Ian Vogel
- Institute for Research in Biomedicine (IRB), Bellinzona, Switzerland
- Università della Svizzera italiana (USI), Lugano, Switzerland
| | - Giada Zoppi
- Institute for Research in Biomedicine (IRB), Bellinzona, Switzerland
- Università della Svizzera italiana (USI), Lugano, Switzerland
| | - Gaia Antonini
- Institute for Research in Biomedicine (IRB), Bellinzona, Switzerland
- Università della Svizzera italiana (USI), Lugano, Switzerland
| | - Tobias Wolf
- Institute for Research in Biomedicine (IRB), Bellinzona, Switzerland
- Università della Svizzera italiana (USI), Lugano, Switzerland
| | - Wenjie Jin
- Institute for Research in Biomedicine (IRB), Bellinzona, Switzerland
- Università della Svizzera italiana (USI), Lugano, Switzerland
| | - Xiaoqin Zheng
- Institute for Research in Biomedicine (IRB), Bellinzona, Switzerland
- Università della Svizzera italiana (USI), Lugano, Switzerland
| | - Giuliano La Barba
- General and Oncologic Surgery, Morgagni-Pierantoni Hospital, Forlì, Italy
| | - Emrullah Birgin
- Department of Surgery, Medical Faculty Mannheim, Universitätsmedizin Mannheim, Heidelberg University, Mannheim, Germany
| | - Marianne Forkel
- Roche Pharma Research and Early Development, Infectious Diseases Discovery, Roche Innovation Center Basel, Basel, Switzerland
| | - Tobias Nilsson
- Roche Pharma Research and Early Development, Infectious Diseases Discovery, Roche Innovation Center Basel, Basel, Switzerland
| | - Romina Marone
- Department of Biomedicine, University of Basel, Basel, Switzerland
- Transplantation Immunology and Nephrology, Basel University Hospital, Basel, Switzerland
| | - Henrik Mueller
- Roche Pharma Research and Early Development, Infectious Diseases Discovery, Roche Innovation Center Basel, Basel, Switzerland
| | - Nadege Pelletier
- Roche Pharma Research and Early Development, Infectious Diseases Discovery, Roche Innovation Center Basel, Basel, Switzerland
| | - Lukas T. Jeker
- Department of Biomedicine, University of Basel, Basel, Switzerland
- Transplantation Immunology and Nephrology, Basel University Hospital, Basel, Switzerland
| | - Gianluca Civenni
- Università della Svizzera italiana (USI), Lugano, Switzerland
- Institute of Oncology Research (IOR), Bellinzona, Switzerland
| | - Christoph Schlapbach
- Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Carlo V. Catapano
- Università della Svizzera italiana (USI), Lugano, Switzerland
- Institute of Oncology Research (IOR), Bellinzona, Switzerland
| | - Lena Seifert
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- National Center for Tumor Diseases (NCT), Dresden, Germany
| | - Adrian M. Seifert
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- National Center for Tumor Diseases (NCT), Dresden, Germany
| | - Silke Gillessen
- Università della Svizzera italiana (USI), Lugano, Switzerland
- Oncology Institute of Southern Switzerland (IOSI), Ente Ospedaliero Cantonale (EOC), Bellinzona, Switzerland
| | - Sara De Dosso
- Università della Svizzera italiana (USI), Lugano, Switzerland
- Oncology Institute of Southern Switzerland (IOSI), Ente Ospedaliero Cantonale (EOC), Bellinzona, Switzerland
| | - Alessandra Cristaudi
- Department of General and Visceral Surgery, Cantonal Hospital Lugano, Lugano, Switzerland
| | - Nuh N. Rahbari
- Department of Surgery, Medical Faculty Mannheim, Universitätsmedizin Mannheim, Heidelberg University, Mannheim, Germany
| | - Giorgio Ercolani
- Department of Medical and Surgical Sciences - DIMEC; Alma Mater Studiorum - Univeristy of Bologna, Bologna, Italy
- Morgagni-Pierantoni Hospital, Ausl Romagna, Forlì, Italy
| | - Roger Geiger
- Institute for Research in Biomedicine (IRB), Bellinzona, Switzerland
- Università della Svizzera italiana (USI), Lugano, Switzerland
- Institute of Oncology Research (IOR), Bellinzona, Switzerland
| |
Collapse
|
|
25
|
Yehya A, Youssef J, Hachem S, Ismael J, Abou-Kheir W. Tissue-specific cancer stem/progenitor cells: Therapeutic implications. World J Stem Cells 2023; 15:323-341. [PMID: 37342220 PMCID: PMC10277968 DOI: 10.4252/wjsc.v15.i5.323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 02/14/2023] [Accepted: 04/12/2023] [Indexed: 05/26/2023] Open
Abstract
Surgical resection, chemotherapy, and radiation are the standard therapeutic modalities for treating cancer. These approaches are intended to target the more mature and rapidly dividing cancer cells. However, they spare the relatively quiescent and intrinsically resistant cancer stem cells (CSCs) subpopulation residing within the tumor tissue. Thus, a temporary eradication is achieved and the tumor bulk tends to revert supported by CSCs' resistant features. Based on their unique expression profile, the identification, isolation, and selective targeting of CSCs hold great promise for challenging treatment failure and reducing the risk of cancer recurrence. Yet, targeting CSCs is limited mainly by the irrelevance of the utilized cancer models. A new era of targeted and personalized anti-cancer therapies has been developed with cancer patient-derived organoids (PDOs) as a tool for establishing pre-clinical tumor models. Herein, we discuss the updated and presently available tissue-specific CSC markers in five highly occurring solid tumors. Additionally, we highlight the advantage and relevance of the three-dimensional PDOs culture model as a platform for modeling cancer, evaluating the efficacy of CSC-based therapeutics, and predicting drug response in cancer patients.
Collapse
Affiliation(s)
- Amani Yehya
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Joe Youssef
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Sana Hachem
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Jana Ismael
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Wassim Abou-Kheir
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut 1107-2020, Lebanon.
| |
Collapse
|
|
26
|
Mai W, Liu Q, Li J, Zheng M, Yan F, Liu H, Lei Y, Xu J, Xu J. Comprehensive analysis of the oncogenic and immunological role of FAP and identification of the ceRNA network in human cancers. Aging (Albany NY) 2023; 15:3738-3758. [PMID: 37166418 PMCID: PMC10449273 DOI: 10.18632/aging.204707] [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: 02/02/2023] [Accepted: 04/22/2023] [Indexed: 05/12/2023]
Abstract
Fibroblast activation protein-alpha (FAP) is a transmembrane serine protease involving in tissue remodeling. Previous studies report that FAP is highly expressed in certain tumors and participated in oncogenesis. However, there is still lack of systematic and in-depth analysis of FAP based on clinical big data. Here, we comprehensively map the FAP expression profile, prognostic outcome, genetic alteration, immune infiltration across over 30 types of human cancers through multiple datasets including TCGA, CPTAC, and cBioPortal. We find that FAP is up-regulated in most cancer types, and increased FAP expression is associated with advanced pathological stages or poor prognosis in several cancers. Furthermore, FAP is significantly correlated with the infiltration of cancer-associated fibroblasts, macrophages, myeloid dendritic cells, as well as endothelia cells. Immunosuppressive checkpoint proteins or cytokines expression, microsatellite instability and tumor mutational burden analysis also indicate the regulation role of FAP in tumor progression. Gene enrichment analysis demonstrates that ECM-receptor interaction as well as extracellular matrix and structure process are linked to the potential mechanism of FAP in tumor pathogenesis. The ceRNA network is also constructed and identified the involvement of LINC00707/hsa-miR-30e-5p/FAP, LINC02535/hsa-miR-30e-5p/FAP, LINC02535/hsa-miR-30d-5p/FAP, as well as AC026356.1/hsa-miR-30d-5p/FAP axis in tumor progression. In conclusion, our study offers new insights into the oncogenic and immunological role of FAP from a pan-cancer perspective, providing new clues for developing novel targeted anti-tumor strategies.
Collapse
Affiliation(s)
- Weiqian Mai
- School of Medicine, School of Life Science and Engineering, Foshan University, Foshan 528000, China
| | - Qingyou Liu
- School of Medicine, School of Life Science and Engineering, Foshan University, Foshan 528000, China
| | - Jiasheng Li
- School of Medicine, School of Life Science and Engineering, Foshan University, Foshan 528000, China
| | - Mincheng Zheng
- Integrative Medicine Research Center, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, University Town, Guangzhou 510006, China
| | - Fuman Yan
- Department of Physiology, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, University Town, Guangzhou 510006, China
| | - Hui Liu
- School of Medicine, School of Life Science and Engineering, Foshan University, Foshan 528000, China
| | - Yuhe Lei
- Department of Pharmacy, Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen 518034, China
| | - Jinwen Xu
- Integrative Medicine Research Center, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, University Town, Guangzhou 510006, China
- Department of Physiology, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, University Town, Guangzhou 510006, China
| | - Jiean Xu
- Integrative Medicine Research Center, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, University Town, Guangzhou 510006, China
- Department of Physiology, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, University Town, Guangzhou 510006, China
| |
Collapse
|
|
27
|
Prakash N, Kim J, Jeon J, Kim S, Arai Y, Bello AB, Park H, Lee SH. Progress and emerging techniques for biomaterial-based derivation of mesenchymal stem cells (MSCs) from pluripotent stem cells (PSCs). Biomater Res 2023; 27:31. [PMID: 37072836 PMCID: PMC10114339 DOI: 10.1186/s40824-023-00371-0] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 03/26/2023] [Indexed: 04/20/2023] Open
Abstract
The use of mesenchymal stem cells (MSCs) for clinical purposes has skyrocketed in the past decade. Their multilineage differentiation potentials and immunomodulatory properties have facilitated the discovery of therapies for various illnesses. MSCs can be isolated from infant and adult tissue sources, which means they are easily available. However, this raises concerns because of the heterogeneity among the various MSC sources, which limits their effective use. Variabilities arise from donor- and tissue-specific differences, such as age, sex, and tissue source. Moreover, adult-sourced MSCs have limited proliferation potentials, which hinders their long-term therapeutic efficacy. These limitations of adult MSCs have prompted researchers to develop a new method for generating MSCs. Pluripotent stem cells (PSCs), such as embryonic stem cells and induced PSCs (iPSCs), can differentiate into various types of cells. Herein, a thorough review of the characteristics, functions, and clinical importance of MSCs is presented. The existing sources of MSCs, including adult- and infant-based sources, are compared. The most recent techniques for deriving MSCs from iPSCs, with a focus on biomaterial-assisted methods in both two- and three-dimensional culture systems, are listed and elaborated. Finally, several opportunities to develop improved methods for efficiently producing MSCs with the aim of advancing their various clinical applications are described.
Collapse
Affiliation(s)
- Nityanand Prakash
- Department of Biomedical Engineering, Dongguk University, Seoul, 04620, Korea
| | - Jiseong Kim
- Department of Biomedical Engineering, Dongguk University, Seoul, 04620, Korea
| | - Jieun Jeon
- Department of Biomedical Engineering, Dongguk University, Seoul, 04620, Korea
| | - Siyeon Kim
- Department of Biomedical Engineering, Dongguk University, Seoul, 04620, Korea
| | - Yoshie Arai
- Department of Biomedical Engineering, Dongguk University, Seoul, 04620, Korea
| | - Alvin Bacero Bello
- Department of Biomedical Engineering, Dongguk University, Seoul, 04620, Korea.
| | - Hansoo Park
- School of Integrative Engineering, Chung-Ang University, Seoul, 06911, Korea.
| | - Soo-Hong Lee
- Department of Biomedical Engineering, Dongguk University, Seoul, 04620, Korea.
| |
Collapse
|
|
28
|
Schroeder JH, Beattie G, Lo JW, Zabinski T, Powell N, Neves JF, Jenner RG, Lord GM. CD90 is not constitutively expressed in functional innate lymphoid cells. Front Immunol 2023; 14:1113735. [PMID: 37114052 PMCID: PMC10126679 DOI: 10.3389/fimmu.2023.1113735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 02/28/2023] [Indexed: 04/29/2023] Open
Abstract
Huge progress has been made in understanding the biology of innate lymphoid cells (ILC) by adopting several well-known concepts in T cell biology. As such, flow cytometry gating strategies and markers, such as CD90, have been applied to indentify ILC. Here, we report that most non-NK intestinal ILC have a high expression of CD90 as expected, but surprisingly a sub-population of cells exhibit low or even no expression of this marker. CD90-negative and CD90-low CD127+ ILC were present amongst all ILC subsets in the gut. The frequency of CD90-negative and CD90-low CD127+ ILC was dependent on stimulatory cues in vitro and enhanced by dysbiosis in vivo. CD90-negative and CD90-low CD127+ ILC were a potential source of IL-13, IFNγ and IL-17A at steady state and upon dysbiosis- and dextran sulphate sodium-elicited colitis. Hence, this study reveals that, contrary to expectations, CD90 is not constitutively expressed by functional ILC in the gut.
Collapse
Affiliation(s)
- Jan-Hendrik Schroeder
- School of Immunology and Microbial Sciences, King’s College London, London, United Kingdom
| | - Gordon Beattie
- Cancer Research UK (CRUK) City of London Centre Single Cell Genomics Facility, University College London Cancer Institute, University College London (UCL), London, United Kingdom
- Genomics Translational Technology Platform, University College London (UCL) Cancer Institute, University College London, London, United Kingdom
| | - Jonathan W. Lo
- School of Immunology and Microbial Sciences, King’s College London, London, United Kingdom
- Division of Digestive Diseases, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Tomasz Zabinski
- School of Immunology and Microbial Sciences, King’s College London, London, United Kingdom
| | - Nick Powell
- Division of Digestive Diseases, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Joana F. Neves
- School of Immunology and Microbial Sciences, King’s College London, London, United Kingdom
| | - Richard G. Jenner
- University College London (UCL) Cancer Institute, University College London, London, United Kingdom
| | - Graham M. Lord
- School of Immunology and Microbial Sciences, King’s College London, London, United Kingdom
- School of Biological Sciences, Faculty of Biology, Medicine and Health, Division of Infection, Immunity and Respiratory Medicine, University of Manchester, Manchester, United Kingdom
| |
Collapse
|
|
29
|
Kim M, Jo KW, Kim H, Han ME, Oh SO. Genetic heterogeneity of liver cancer stem cells. Anat Cell Biol 2023; 56:94-108. [PMID: 36384888 PMCID: PMC9989795 DOI: 10.5115/acb.22.161] [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: 08/22/2022] [Revised: 10/27/2022] [Accepted: 10/27/2022] [Indexed: 11/19/2022] Open
Abstract
Cancer cell heterogeneity is a serious problem in the control of tumor progression because it can cause chemoresistance and metastasis. Heterogeneity can be generated by various mechanisms, including genetic evolution of cancer cells, cancer stem cells (CSCs), and niche heterogeneity. Because the genetic heterogeneity of CSCs has been poorly characterized, the genetic mutation status of CSCs was examined using Exome-Seq and RNA-Seq data of liver cancer. Here we show that different surface markers for liver cancer stem cells (LCSCs) showed a unique propensity for genetic mutations. Cluster of differentiation 133 (CD133)-positive cells showed frequent mutations in the IRF2, BAP1, and ERBB3 genes. However, leucine-rich repeat-containing G protein-coupled receptor 5-positive cells showed frequent mutations in the CTNNB1, RELN, and ROBO1 genes. In addition, some genetic mutations were frequently observed irrespective of the surface markers for LCSCs. BAP1 mutations was frequently observed in CD133-, CD24-, CD13-, CD90-, epithelial cell adhesion molecule-, or keratin 19-positive LCSCs. ASXL2, ERBB3, IRF2, TLX3, CPS1, and NFATC2 mutations were observed in more than three types of LCSCs, suggesting that common mechanisms for the development of these LCSCs. The present study provides genetic heterogeneity depending on the surface markers for LCSCs. The genetic heterogeneity of LCSCs should be considered in the development of LCSC-targeting therapeutics.
Collapse
Affiliation(s)
- Minjeong Kim
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan, Korea
| | - Kwang-Woo Jo
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan, Korea
| | - Hyojin Kim
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan, Korea
| | - Myoung-Eun Han
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan, Korea
| | - Sae-Ock Oh
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan, Korea
| |
Collapse
|
|
30
|
A Simplified and Effective Approach for the Isolation of Small Pluripotent Stem Cells Derived from Human Peripheral Blood. Biomedicines 2023; 11:biomedicines11030787. [PMID: 36979766 PMCID: PMC10045871 DOI: 10.3390/biomedicines11030787] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Revised: 02/24/2023] [Accepted: 03/03/2023] [Indexed: 03/08/2023] Open
Abstract
Pluripotent stem cells are key players in regenerative medicine. Embryonic pluripotent stem cells, despite their significant advantages, are associated with limitations such as their inadequate availability and the ethical dilemmas in their isolation and clinical use. The discovery of very small embryonic-like (VSEL) stem cells addressed the aforementioned limitations, but their isolation technique remains a challenge due to their small cell size and their efficiency in isolation. Here, we report a simplified and effective approach for the isolation of small pluripotent stem cells derived from human peripheral blood. Our approach results in a high yield of small blood stem cell (SBSC) population, which expresses pluripotent embryonic markers (e.g., Nanog, SSEA-3) and the Yamanaka factors. Further, a fraction of SBSCs also co-express hematopoietic markers (e.g., CD45 and CD90) and/or mesenchymal markers (e.g., CD29, CD105 and PTH1R), suggesting a mixed stem cell population. Finally, quantitative proteomic profiling reveals that SBSCs contain various stem cell markers (CD9, ITGA6, MAPK1, MTHFD1, STAT3, HSPB1, HSPA4), and Transcription reg complex factors (e.g., STAT5B, PDLIM1, ANXA2, ATF6, CAMK1). In conclusion, we present a novel, simplified and effective isolating process that yields an abundant population of small-sized cells with characteristics of pluripotency from human peripheral blood.
Collapse
|
|
31
|
Zeng F, Gao M, Liao S, Zhou Z, Luo G, Zhou Y. Role and mechanism of CD90 + fibroblasts in inflammatory diseases and malignant tumors. Mol Med 2023; 29:20. [PMID: 36747131 PMCID: PMC9900913 DOI: 10.1186/s10020-023-00616-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Accepted: 01/29/2023] [Indexed: 02/08/2023] Open
Abstract
Fibroblasts are highly heterogeneous mesenchymal stromal cells, and different fibroblast subpopulations play different roles. A subpopulation of fibroblasts expressing CD90, a 25-37 kDa glycosylphosphatidylinositol anchored protein, plays a dominant role in the fibrotic and pro-inflammatory state. In this review, we focused on CD90+ fibroblasts, and their roles and possible mechanisms in disease processes. First, the main biological functions of CD90+ fibroblasts in inducing angiogenesis and maintaining tissue homeostasis are described. Second, the role and possible mechanism of CD90+ fibroblasts in inducing pulmonary fibrosis, inflammatory arthritis, inflammatory skin diseases, and scar formation are introduced, and we discuss how CD90+ cancer-associated fibroblasts might serve as promising cancer biomarkers. Finally, we propose future research directions related to CD90+ fibroblasts. This review will provide a theoretical basis for the diagnosis and treatment CD90+ fibroblast-related disease.
Collapse
Affiliation(s)
- Feng Zeng
- grid.216417.70000 0001 0379 7164NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013 Hunan China ,grid.216417.70000 0001 0379 7164Cancer Research Institute, Basic School of Medicine, Central South University, Changsha, 410078 Hunan China
| | - Mengxiang Gao
- grid.216417.70000 0001 0379 7164NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013 Hunan China ,grid.216417.70000 0001 0379 7164Cancer Research Institute, Basic School of Medicine, Central South University, Changsha, 410078 Hunan China
| | - Shan Liao
- grid.216417.70000 0001 0379 7164Department of Pathology, The Third Xiangya Hospital, Central South University, Changsha, 410013 Hunan China
| | - Zihua Zhou
- grid.508130.fDepartment of Oncology, Loudi Central Hospital, Loudi, 417000 China
| | - Gengqiu Luo
- Department of Pathology, Xiangya Hospital, Basic School of Medicine, Central South University, No. 88 of Xiangya Road, Changsha, 410008, Hunan, China.
| | - Yanhong Zhou
- NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China. .,Cancer Research Institute, Basic School of Medicine, Central South University, Changsha, 410078, Hunan, China.
| |
Collapse
|
|
32
|
Al-Holou WN, Wang H, Ravikumar V, Shankar S, Oneka M, Fehmi Z, Verhaak RG, Kim H, Pratt D, Camelo-Piragua S, Speers C, Wahl DR, Hollon T, Sagher O, Heth JA, Muraszko KM, Lawrence TS, de Carvalho AC, Mikkelsen T, Rao A, Rehemtulla A. Subclonal evolution and expansion of spatially distinct THY1-positive cells is associated with recurrence in glioblastoma. Neoplasia 2023; 36:100872. [PMID: 36621024 PMCID: PMC9841165 DOI: 10.1016/j.neo.2022.100872] [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: 12/19/2022] [Accepted: 12/22/2022] [Indexed: 01/07/2023]
Abstract
PURPOSE Glioblastoma(GBM) is a lethal disease characterized by inevitable recurrence. Here we investigate the molecular pathways mediating resistance, with the goal of identifying novel therapeutic opportunities. EXPERIMENTAL DESIGN We developed a longitudinal in vivo recurrence model utilizing patient-derived explants to produce paired specimens(pre- and post-recurrence) following temozolomide(TMZ) and radiation(IR). These specimens were evaluated for treatment response and to identify gene expression pathways driving treatment resistance. Findings were clinically validated using spatial transcriptomics of human GBMs. RESULTS These studies reveal in replicate cohorts, a gene expression profile characterized by upregulation of mesenchymal and stem-like genes at recurrence. Analyses of clinical databases revealed significant association of this transcriptional profile with worse overall survival and upregulation at recurrence. Notably, gene expression analyses identified upregulation of TGFβ signaling, and more than one-hundred-fold increase in THY1 levels at recurrence. Furthermore, THY1-positive cells represented <10% of cells in treatment-naïve tumors, compared to 75-96% in recurrent tumors. We then isolated THY1-positive cells from treatment-naïve patient samples and determined that they were inherently resistant to chemoradiation in orthotopic models. Additionally, using image-guided biopsies from treatment-naïve human GBM, we conducted spatial transcriptomic analyses. This revealed rare THY1+ regions characterized by mesenchymal/stem-like gene expression, analogous to our recurrent mouse model, which co-localized with macrophages within the perivascular niche. We then inhibited TGFBRI activity in vivo which decreased mesenchymal/stem-like protein levels, including THY1, and restored sensitivity to TMZ/IR in recurrent tumors. CONCLUSIONS These findings reveal that GBM recurrence may result from tumor repopulation by pre-existing, therapy-resistant, THY1-positive, mesenchymal cells within the perivascular niche.
Collapse
Affiliation(s)
- Wajd N Al-Holou
- Department of Neurosurgery, University of Michigan, Ann Arbor, MI 48109, United States
| | - Hanxiao Wang
- Department of Radiation Oncology, University of Michigan, NCRC 520, Room 1342, Ann Arbor, MI 48105, United States; AstraZeneca, United States
| | - Visweswaran Ravikumar
- Department of Computational Medicine & Bioinformatics, The University of Michigan Medical School, Ann Arbor, MI 48109, United States
| | - Sunita Shankar
- Department of Neurosurgery, University of Michigan, Ann Arbor, MI 48109, United States
| | - Morgan Oneka
- Department of Computational Medicine & Bioinformatics, The University of Michigan Medical School, Ann Arbor, MI 48109, United States
| | - Ziad Fehmi
- Department of Neurosurgery, University of Michigan, Ann Arbor, MI 48109, United States
| | | | - Hoon Kim
- The Jackson Laboratory, Farmington, CT 06032, United States; Department of Biopharmaceutical Convergence, Sungkyunkwan University, South Korea
| | - Drew Pratt
- Department of Pathology, University of Michigan, United States
| | | | - Corey Speers
- Department of Radiation Oncology, University of Michigan, NCRC 520, Room 1342, Ann Arbor, MI 48105, United States
| | - Daniel R Wahl
- Department of Radiation Oncology, University of Michigan, NCRC 520, Room 1342, Ann Arbor, MI 48105, United States
| | - Todd Hollon
- Department of Neurosurgery, University of Michigan, Ann Arbor, MI 48109, United States
| | - Oren Sagher
- Department of Neurosurgery, University of Michigan, Ann Arbor, MI 48109, United States
| | - Jason A Heth
- Department of Neurosurgery, University of Michigan, Ann Arbor, MI 48109, United States
| | - Karin M Muraszko
- Department of Neurosurgery, University of Michigan, Ann Arbor, MI 48109, United States
| | - Theodore S Lawrence
- Department of Radiation Oncology, University of Michigan, NCRC 520, Room 1342, Ann Arbor, MI 48105, United States
| | - Ana C de Carvalho
- Department of Neurosurgery, Henry Ford Hospital, Detroit, MI 48202, United States
| | - Tom Mikkelsen
- Department of Neurosurgery, Henry Ford Hospital, Detroit, MI 48202, United States
| | - Arvind Rao
- Department of Radiation Oncology, University of Michigan, NCRC 520, Room 1342, Ann Arbor, MI 48105, United States; Department of Computational Medicine & Bioinformatics, The University of Michigan Medical School, Ann Arbor, MI 48109, United States
| | - Alnawaz Rehemtulla
- Department of Radiation Oncology, University of Michigan, NCRC 520, Room 1342, Ann Arbor, MI 48105, United States.
| |
Collapse
|
|
33
|
Wolfmeier H, Heindl S, Platzl C, Kaser-Eichberger A, Nematian-Ardestani E, Strohmaier C, Pruszak J, Schroedl F. Targeted surface marker screening on neuronal structures in the human choroid. Exp Eye Res 2023; 227:109368. [PMID: 36586549 DOI: 10.1016/j.exer.2022.109368] [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: 09/02/2022] [Revised: 12/23/2022] [Accepted: 12/26/2022] [Indexed: 12/30/2022]
Abstract
While choroidal neuronal control is known to be essential for retinal and ocular health, its mechanisms are not understood. Especially, the local choroidal innervation mediated by intrinsic choroidal neurons (ICN) remains enigmatic. Neuronal functionality depends on the synaptic neurotransmitters and neuroregulatory peptides involved as well as from membrane components presented on the cell surface. Since the neuronal surface molecular expression patterns in the choroid are currently unknown, we sought to determine the presence of various cluster-of-differentiation (CD) antigens in choroidal neuronal structures with a particular focus on ICN. Human choroids were prepared for immunohistochemistry and the pan-neuronal marker PGP9.5 was combined with CD15, CD24, CD29, CD34, CD46, CD49b, CD49e, CD56, CD58, CD59, CD71, CD81, CD90, CD146, CD147, CD151, CD165, CD171, CD184, CD200, CD271 and fluorescence- and confocal laser scanning-microscopy was used for documentation. The following antigens were found to be co-localized in PGP.9.5+ nerve fibers and ICN perikarya: CD29, CD34, CD56, CD81, CD90, CD146, CD147, CD151, CD171, CD200 and CD271, while all other CD markers where not detectable. Whereas CD24- and CD59- immunoreactivity was clearly absent in ICN perikarya, some neural processes of the choroidal stroma displayed CD24 and CD59 immunopositivity. While a multitude of the aforementioned CD-markers were indeed detected in nervous structures of the choroid, the CD24+ and CD59+ nerve fibers most likely have extrinsic origin from cranial ganglia since ICN cell bodies were found to lack both markers. These findings illustrate how the detailed analysis of CD molecules described here opens novel avenues for future functional studies on choroidal innervation and its control.
Collapse
Affiliation(s)
- H Wolfmeier
- Center for Anatomy and Cell Biology, Institute of Anatomy and Cell Biology - Salzburg, Paracelsus Medical University, Salzburg, Austria
| | - S Heindl
- Center for Anatomy and Cell Biology, Institute of Anatomy and Cell Biology - Salzburg, Paracelsus Medical University, Salzburg, Austria
| | - C Platzl
- Center for Anatomy and Cell Biology, Institute of Anatomy and Cell Biology - Salzburg, Paracelsus Medical University, Salzburg, Austria
| | - A Kaser-Eichberger
- Center for Anatomy and Cell Biology, Institute of Anatomy and Cell Biology - Salzburg, Paracelsus Medical University, Salzburg, Austria
| | - E Nematian-Ardestani
- Center for Anatomy and Cell Biology, Institute of Anatomy and Cell Biology - Salzburg, Paracelsus Medical University, Salzburg, Austria
| | - C Strohmaier
- Department of Ophthalmology and Optometry, Johannes Kepler University, Linz, Austria
| | - J Pruszak
- Center for Anatomy and Cell Biology, Institute of Anatomy and Cell Biology - Salzburg, Paracelsus Medical University, Salzburg, Austria
| | - F Schroedl
- Center for Anatomy and Cell Biology, Institute of Anatomy and Cell Biology - Salzburg, Paracelsus Medical University, Salzburg, Austria.
| |
Collapse
|
|
34
|
Chiu HW, Hung SW, Chiu CF, Hong JR. A Mitochondrion-Targeting Protein (B2) Primes ROS/Nrf2-Mediated Stress Signals, Triggering Apoptosis and Necroptosis in Lung Cancer. Biomedicines 2023; 11:biomedicines11010186. [PMID: 36672696 PMCID: PMC9855812 DOI: 10.3390/biomedicines11010186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 01/03/2023] [Accepted: 01/09/2023] [Indexed: 01/15/2023] Open
Abstract
The betanodavirus B2 protein targets mitochondria and triggers mitochondrion-mediated cell death signaling in lung cancer cells; however, its molecular mechanism remains unknown. In this study, we observed that B2 triggers hydrogen peroxide/Nrf2-involved stress signals in the dynamic regulation of non-small lung cancer cell (NSCLC)-programmed cell death. Here, the B2 protein works as a necrotic inducer that triggers lung cancer death via p53 upregulation and RIP3 expression, suggesting a new perspective on lung cancer therapy. We employed the B2 protein to target A549 lung cancer cells and solid tumors in NOD/SCID mice. Tumors were collected and processed for the hematoxylin and eosin staining of tissue and cell sections, and their sera were used for blood biochemistry analysis. We observed that B2 killed an A549 cell-induced solid tumor in NOD/SCID mice; however, the mutant ΔB2 did not. In NOD/SCID mice, B2 (but not ΔB2) induced both p53/Bax-mediated apoptosis and RIPK3-mediated necroptosis. Finally, immunochemistry analysis showed hydrogen peroxide /p38/Nrf2 stress strongly inhibited the production of tumor markers CD133, Thy1, and napsin, which correlate with migration and invasion in cancer cells. This B2-triggered, ROS/Nrf2-mediated stress signal triggered multiple signals via pathways that killed A549 lung cancer tumor cells in vivo. Our results provide novel insight into lung cancer management and drug therapy.
Collapse
Affiliation(s)
- Hsuan-Wen Chiu
- Laboratory of Molecular Virology and Biotechnology, Institute of Biotechnology, National Cheng Kung University, Tainan 701, Taiwan
- Department of Biotechnology and Bioindustry, National Cheng Kung University, Tainan 701, Taiwan
| | - Shao-Wen Hung
- Division of Animal Industry, Animal Technology Research Center, Agricultural Technology Research Institute, Hsinchu 300, Taiwan
| | - Ching-Feng Chiu
- Graduate Institute of Metabolism and Obesity Sciences, College of Nutrition, Taipei Medical University, Taipei 11031, Taiwan
- Graduate TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Jiann-Ruey Hong
- Laboratory of Molecular Virology and Biotechnology, Institute of Biotechnology, National Cheng Kung University, Tainan 701, Taiwan
- Department of Biotechnology and Bioindustry, National Cheng Kung University, Tainan 701, Taiwan
- Correspondence: ; Tel.: +886-6-2003082; Fax: +886-6-2766505
| |
Collapse
|
|
35
|
Li H, Wang D, Zhou X, Ding S, Guo W, Zhang S, Li Z, Huang T, Cai YD. Characterization of spleen and lymph node cell types via CITE-seq and machine learning methods. Front Mol Neurosci 2022; 15:1033159. [PMID: 36311013 PMCID: PMC9608858 DOI: 10.3389/fnmol.2022.1033159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 09/26/2022] [Indexed: 11/13/2022] Open
Abstract
The spleen and lymph nodes are important functional organs for human immune system. The identification of cell types for spleen and lymph nodes is helpful for understanding the mechanism of immune system. However, the cell types of spleen and lymph are highly diverse in the human body. Therefore, in this study, we employed a series of machine learning algorithms to computationally analyze the cell types of spleen and lymph based on single-cell CITE-seq sequencing data. A total of 28,211 cell data (training vs. test = 14,435 vs. 13,776) involving 24 cell types were collected for this study. For the training dataset, it was analyzed by Boruta and minimum redundancy maximum relevance (mRMR) one by one, resulting in an mRMR feature list. This list was fed into the incremental feature selection (IFS) method, incorporating four classification algorithms (deep forest, random forest, K-nearest neighbor, and decision tree). Some essential features were discovered and the deep forest with its optimal features achieved the best performance. A group of related proteins (CD4, TCRb, CD103, CD43, and CD23) and genes (Nkg7 and Thy1) contributing to the classification of spleen and lymph nodes cell types were analyzed. Furthermore, the classification rules yielded by decision tree were also provided and analyzed. Above findings may provide helpful information for deepening our understanding on the diversity of cell types.
Collapse
Affiliation(s)
- Hao Li
- College of Biological and Food Engineering, Jilin Engineering Normal University, Changchun, China
| | - Deling Wang
- State Key Laboratory of Oncology in South China, Department of Radiology, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xianchao Zhou
- Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shijian Ding
- School of Life Sciences, Shanghai University, Shanghai, China
| | - Wei Guo
- Key Laboratory of Stem Cell Biology, Shanghai Institutes for Biological Sciences (SIBS), Shanghai Jiao Tong University School of Medicine (SJTUSM), Chinese Academy of Sciences (CAS), Shanghai, China
| | - Shiqi Zhang
- Department of Biostatistics, University of Copenhagen, Copenhagen, Denmark
| | - Zhandong Li
- College of Biological and Food Engineering, Jilin Engineering Normal University, Changchun, China
| | - Tao Huang
- CAS Key Laboratory of Computational Biology, Bio-Med Big Data Center, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
- *Correspondence: Tao Huang,
| | - Yu-Dong Cai
- School of Life Sciences, Shanghai University, Shanghai, China
- Yu-Dong Cai,
| |
Collapse
|
|
36
|
Rix B, Maduro AH, Bridge KS, Grey W. Markers for human haematopoietic stem cells: The disconnect between an identification marker and its function. Front Physiol 2022; 13:1009160. [PMID: 36246104 PMCID: PMC9564379 DOI: 10.3389/fphys.2022.1009160] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 08/22/2022] [Indexed: 11/13/2022] Open
Abstract
The haematopoietic system is a classical stem cell hierarchy that maintains all the blood cells in the body. Haematopoietic stem cells (HSCs) are rare, highly potent cells that reside at the apex of this hierarchy and are historically some of the most well studied stem cells in humans and laboratory models, with haematopoiesis being the original system to define functional cell types by cell surface markers. Whilst it is possible to isolate HSCs to near purity, we know very little about the functional activity of markers to purify HSCs. This review will focus on the historical efforts to purify HSCs in humans based on cell surface markers, their putative functions and recent advances in finding functional markers on HSCs.
Collapse
Affiliation(s)
| | | | | | - William Grey
- *Correspondence: Katherine S. Bridge, ; William Grey,
| |
Collapse
|
|
37
|
The Nervous System as a Regulator of Cancer Hallmarks: Insights into Therapeutic Implications. Cancers (Basel) 2022; 14:cancers14184372. [PMID: 36139532 PMCID: PMC9496837 DOI: 10.3390/cancers14184372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 09/05/2022] [Accepted: 09/06/2022] [Indexed: 11/17/2022] Open
Abstract
Simple Summary The nervous system communicates with the whole organism, regulating several physiological pathways. The modification of nerve activity could deregulate the state of cellular and tissue homeostasis which could drive cancer development. This paper provides the current state of knowledge, in an evidence-oriented manner, that the nervous system is able to participate in the carcinogenesis process by inducing biochemical, physiological, and cellular modifications involved in the hallmarks of cancer. Abstract The involvement of the nervous system in the development of cancer is controversial. Several authors have shown opinions and conflicting evidence that support the early effect of the nervous system on the carcinogenic process. For about a century, research has not been enough, questions remain open, ideas are not discarded, and although more research is still needed to answer all the questions, there is now enough evidence to support the theories and give hope of finding one more possible form of treatment. It is clear that malignant neoplasms have endogenous characteristics that allow them to establish and progress. Some of these characteristics known as hallmarks of cancer, are damage mechanisms in the pathology but necessary during other physiological processes which show some nerve dependence. The nervous system communicates with the whole organism, regulating physiological processes necessary to respond to external stimuli and for the maintenance of homeostasis. The modification of nerve activity could generate an overload and deregulate the state of cellular and tissue homeostasis; this could drive cancer development. In this review, we will address the issue in an evidence-oriented manner that supports that the nervous system is able to participate in the initial and progressive process of carcinogenesis by inducing biochemical, physiological, and cellular modifications involved in the hallmarks of cancer.
Collapse
|
|
38
|
Zhou Y, Meng X, He W, Li X, Zhao R, Dong C, Yuan D, Yang J, Zhang R, Shi G, Huang Y, Liu J, Liu J, Liu S, Fu P, Sun M. USF1/CD90 signaling in maintaining glioblastoma stem cells and tumor-associated macrophages adhesion. Neuro Oncol 2022; 24:1482-1493. [PMID: 35287174 PMCID: PMC10167418 DOI: 10.1093/neuonc/noac063] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Glioblastoma stem cells (GSCs) and their interplay with tumor-associated macrophages (TAMs) are responsible for malignant growth and tumor recurrence of glioblastoma multiforme (GBM), but the underlying mechanisms are largely unknown. METHODS Cell viability, stemness, migration, and invasion were measured in GSCs after the knockdown of upstream stimulating factor 1 (USF1). Luciferase assay and chromatin immunoprecipitation qPCR were performed to determine the regulation of CD90 by USF1. Immunohistochemistry and immunofluorescent staining were used to examine the expression of USF1 and GSC markers, as well as the crosstalk between GSCs and TAMs. In addition, the interaction between GSCs and TAMs was confirmed using in vivo GBM models. RESULTS We show that USF1 promotes malignant glioblastoma phenotypes and GSCs-TAMs physical interaction by inducing CD90 expression. USF1 predicts a poor prognosis for glioma patients and is upregulated in patient-derived GSCs and glioblastoma cell lines. USF1 overexpression increases the proliferation, invasion, and neurosphere formation of GSCs and glioblastoma cell lines, while USF1 knockdown exerts an opposite effect. Further mechanistic studies reveal that USF1 promotes GSC stemness by directly regulating CD90 expression. Importantly, CD90 of GSCs functions as an anchor for physical interaction with macrophages. Additionally, the USF1/CD90 signaling axis supports the GSCs and TAMs adhesion and immunosuppressive feature of TAMs, which in turn enhance the stemness of GSCs. Moreover, the overexpression of CD90 restores the stemness property in USF1 knockdown GSCs and its immunosuppressive microenvironment. CONCLUSIONS Our findings indicate that the USF1/CD90 axis might be a potential therapeutic target for the treatment of glioblastoma.
Collapse
Affiliation(s)
- Yuanshuai Zhou
- Jiangsu Key Laboratory of Medical Optics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, China
| | - Xingjun Meng
- Jiangsu Key Laboratory of Medical Optics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, China
| | - Wen He
- Jiangsu Key Laboratory of Medical Optics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, China
| | - Xinying Li
- Department of Biochemistry and Molecular Biology, Shandong University School of Basic Medical Sciences, Jinan, China
| | - Rongchuan Zhao
- Jiangsu Key Laboratory of Medical Optics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, China
- School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Caihua Dong
- Jiangsu Key Laboratory of Medical Optics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, China
- School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Detian Yuan
- Department of Biochemistry and Molecular Biology, Shandong University School of Basic Medical Sciences, Jinan, China
| | - Jiao Yang
- Jiangsu Key Laboratory of Medical Optics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, China
| | - Ruobing Zhang
- Jiangsu Key Laboratory of Medical Optics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, China
| | - Guohua Shi
- Jiangsu Key Laboratory of Medical Optics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, China
| | - Yulun Huang
- Department of Neurosurgery, Dushu Lake Hospital Affiliated of Soochow University, Suzhou, China
- Department of Neurosurgery, Medical Center of Soochow University, Suzhou, China
- Department of Neurosurgery and Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jiangang Liu
- Department of Neurosurgery and Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jianping Liu
- Department of Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Songbai Liu
- Suzhou Key Laboratory of Medical Biotechnology, Suzhou Vocational Health College, Suzhou, China
| | - Peng Fu
- Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Minxuan Sun
- Jiangsu Key Laboratory of Medical Optics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, China
- School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| |
Collapse
|
|
39
|
Glabman RA, Choyke PL, Sato N. Cancer-Associated Fibroblasts: Tumorigenicity and Targeting for Cancer Therapy. Cancers (Basel) 2022; 14:cancers14163906. [PMID: 36010899 PMCID: PMC9405783 DOI: 10.3390/cancers14163906] [Citation(s) in RCA: 127] [Impact Index Per Article: 42.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 08/09/2022] [Accepted: 08/10/2022] [Indexed: 11/24/2022] Open
Abstract
Simple Summary Cancer-associated fibroblasts (CAFs) are found in the tumor microenvironment and exhibit several protumorigenic functions. Preclinical studies suggest that CAFs can be reduced, eliminated, or reprogrammed; however, clinical translation has not yet occurred. A better understanding of these cells and their functions will undoubtedly improve cancer treatments. In this review, we summarize current research, highlight major challenges, and discuss future opportunities for improving our knowledge of CAF biology and targeting. Abstract Cancer-associated fibroblasts (CAFs) are a heterogenous group of activated fibroblasts and a major component of the tumor stroma. CAFs may be derived from fibroblasts, epithelial cells, endothelial cells, cancer stem cells, adipocytes, pericytes, or stellate cells. These complex origins may underlie their functional diversity, which includes pro-tumorigenic roles in extracellular matrix remodeling, the suppression of anti-tumor immunity, and resistance to cancer therapy. Several methods for targeting CAFs to inhibit tumor progression and enhance anti-tumor immunity have recently been reported. While preclinical studies have shown promise, to date they have been unsuccessful in human clinical trials against melanoma, breast cancer, pancreas cancer, and colorectal cancers. This review summarizes recent and major advances in CAF-targeting therapies, including DNA-based vaccines, anti-CAF CAR-T cells, and modifying and reprogramming CAF functions. The challenges in developing effective anti-CAF treatment are highlighted, which include CAF heterogeneity and plasticity, the lack of specific target markers for CAFs, the limitations in animal models recapitulating the human cancer microenvironment, and the undesirable off-target and systemic side effects. Overcoming these challenges and expanding our understanding of the basic biology of CAFs is necessary for making progress towards safe and effective therapeutic strategies against cancers in human patients.
Collapse
Affiliation(s)
- Raisa A. Glabman
- Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
- Department of Comparative Medicine and Integrative Biology, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USA
| | - Peter L. Choyke
- Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Noriko Sato
- Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
- Correspondence: ; Tel.: +1-240-858-3079
| |
Collapse
|
|
40
|
THY1-mediated mechanisms converge to drive YAP activation in skin homeostasis and repair. Nat Cell Biol 2022; 24:1049-1063. [PMID: 35798842 DOI: 10.1038/s41556-022-00944-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Accepted: 05/18/2022] [Indexed: 12/24/2022]
Abstract
Anchored cells of the basal epidermis constantly undergo proliferation in an overcrowded environment. An important regulator of epidermal proliferation is YAP, which can be controlled by both cell-matrix and cell-cell interactions. Here, we report that THY1, a GPI-anchored protein, inhibits epidermal YAP activity through converging molecular mechanisms. THY1 deficiency leads to increased adhesion by activating the integrin-β1-SRC module. Notably, regardless of high cellular densities, the absence of THY1 leads to the dissociation of an adherens junction complex that enables the release and translocation of YAP. Due to increased YAP-dependent proliferation, Thy1-/- mice display enhanced wound repair and hair follicle regeneration. Taken together, our work reveals THY1 as a crucial regulator of cell-matrix and cell-cell interactions that controls YAP activity in skin homeostasis and regeneration.
Collapse
|
|
41
|
Raghubar AM, Pham DT, Tan X, Grice LF, Crawford J, Lam PY, Andersen SB, Yoon S, Teoh SM, Matigian NA, Stewart A, Francis L, Ng MSY, Healy HG, Combes AN, Kassianos AJ, Nguyen Q, Mallett AJ. Spatially Resolved Transcriptomes of Mammalian Kidneys Illustrate the Molecular Complexity and Interactions of Functional Nephron Segments. Front Med (Lausanne) 2022; 9:873923. [PMID: 35872784 PMCID: PMC9300864 DOI: 10.3389/fmed.2022.873923] [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: 02/11/2022] [Accepted: 05/23/2022] [Indexed: 11/30/2022] Open
Abstract
Available transcriptomes of the mammalian kidney provide limited information on the spatial interplay between different functional nephron structures due to the required dissociation of tissue with traditional transcriptome-based methodologies. A deeper understanding of the complexity of functional nephron structures requires a non-dissociative transcriptomics approach, such as spatial transcriptomics sequencing (ST-seq). We hypothesize that the application of ST-seq in normal mammalian kidneys will give transcriptomic insights within and across species of physiology at the functional structure level and cellular communication at the cell level. Here, we applied ST-seq in six mice and four human kidneys that were histologically absent of any overt pathology. We defined the location of specific nephron structures in the captured ST-seq datasets using three lines of evidence: pathologist's annotation, marker gene expression, and integration with public single-cell and/or single-nucleus RNA-sequencing datasets. We compared the mouse and human cortical kidney regions. In the human ST-seq datasets, we further investigated the cellular communication within glomeruli and regions of proximal tubules-peritubular capillaries by screening for co-expression of ligand-receptor gene pairs. Gene expression signatures of distinct nephron structures and microvascular regions were spatially resolved within the mouse and human ST-seq datasets. We identified 7,370 differentially expressed genes (p adj < 0.05) distinguishing species, suggesting changes in energy production and metabolism in mouse cortical regions relative to human kidneys. Hundreds of potential ligand-receptor interactions were identified within glomeruli and regions of proximal tubules-peritubular capillaries, including known and novel interactions relevant to kidney physiology. Our application of ST-seq to normal human and murine kidneys confirms current knowledge and localization of transcripts within the kidney. Furthermore, the generated ST-seq datasets provide a valuable resource for the kidney community that can be used to inform future research into this complex organ.
Collapse
Affiliation(s)
- Arti M. Raghubar
- Kidney Health Service, Royal Brisbane and Women's Hospital, Herston, QLD, Australia
- Conjoint Internal Medicine Laboratory, Chemical Pathology, Pathology Queensland, Health Support Queensland, Herston, QLD, Australia
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
- Anatomical Pathology, Pathology Queensland, Health Support Queensland, Herston, QLD, Australia
- Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
| | - Duy T. Pham
- Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
| | - Xiao Tan
- Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
| | - Laura F. Grice
- Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
- School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia
| | - Joanna Crawford
- Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
| | - Pui Yeng Lam
- Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
| | - Stacey B. Andersen
- Genome Innovation Hub, University of Queensland, Brisbane, QLD, Australia
- UQ Sequencing Facility, Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
| | - Sohye Yoon
- Genome Innovation Hub, University of Queensland, Brisbane, QLD, Australia
| | - Siok Min Teoh
- UQ Diamantina Institute, Faculty of Medicine, The University of Queensland, Woolloongabba, QLD, Australia
| | - Nicholas A. Matigian
- QCIF Facility for Advanced Bioinformatics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
| | - Anne Stewart
- Anatomical Pathology, Pathology Queensland, Health Support Queensland, Herston, QLD, Australia
| | - Leo Francis
- Anatomical Pathology, Pathology Queensland, Health Support Queensland, Herston, QLD, Australia
| | - Monica S. Y. Ng
- Kidney Health Service, Royal Brisbane and Women's Hospital, Herston, QLD, Australia
- Conjoint Internal Medicine Laboratory, Chemical Pathology, Pathology Queensland, Health Support Queensland, Herston, QLD, Australia
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
- Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
- Nephrology Department, Princess Alexandra Hospital, Woolloongabba, QLD, Australia
| | - Helen G. Healy
- Kidney Health Service, Royal Brisbane and Women's Hospital, Herston, QLD, Australia
- Conjoint Internal Medicine Laboratory, Chemical Pathology, Pathology Queensland, Health Support Queensland, Herston, QLD, Australia
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
| | - Alexander N. Combes
- Department of Anatomy and Developmental Biology, Stem Cells and Development Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia
| | - Andrew J. Kassianos
- Kidney Health Service, Royal Brisbane and Women's Hospital, Herston, QLD, Australia
- Conjoint Internal Medicine Laboratory, Chemical Pathology, Pathology Queensland, Health Support Queensland, Herston, QLD, Australia
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
| | - Quan Nguyen
- Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
| | - Andrew J. Mallett
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
- Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
- College of Medicine & Dentistry, James Cook University, Townsville, Queensland, QLD, Australia
- Department of Renal Medicine, Townsville University Hospital, Townsville, Queensland, QLD, Australia
| |
Collapse
|
|
42
|
Tourigny DS, Zucker M, Kim M, Russo P, Coleman J, Lee CH, Carlo MI, Chen YB, Hakimi AA, Kotecha RR, Reznik E. Molecular Characterization of the Tumor Microenvironment in Renal Medullary Carcinoma. Front Oncol 2022; 12:910147. [PMID: 35837094 PMCID: PMC9275834 DOI: 10.3389/fonc.2022.910147] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 05/27/2022] [Indexed: 11/13/2022] Open
Abstract
Renal medullary carcinoma (RMC) is a highly aggressive disease associated with sickle hemoglobinopathies and universal loss of the tumor suppressor gene SMARCB1. RMC has a relatively low rate of incidence compared with other renal cell carcinomas (RCCs) that has hitherto made molecular profiling difficult. To probe this rare disease in detail we performed an in-depth characterization of the RMC tumor microenvironment using a combination of genomic, metabolic and single-cell RNA-sequencing experiments on tissue from a representative untreated RMC patient, complemented by retrospective analyses of archival tissue and existing published data. Our study of the tumor identifies a heterogenous population of malignant cell states originating from the thick ascending limb of the Loop of Henle within the renal medulla. Transformed RMC cells displayed the hallmarks of increased resistance to cell death by ferroptosis and proteotoxic stress driven by MYC-induced proliferative signals. Specifically, genomic characterization of RMC tumors provides substantiating evidence for the recently proposed dependence of SMARCB1-difficient cancers on proteostasis modulated by an intact CDKN2A-p53 pathway. We also provide evidence that increased cystine-mTORC-GPX4 signaling plays a role in protecting transformed RMC cells against ferroptosis. We further propose that RMC has an immune landscape comparable to that of untreated RCCs, including heterogenous expression of the immune ligand CD70 within a sub-population of tumor cells. The latter could provide an immune-modulatory role that serves as a viable candidate for therapeutic targeting.
Collapse
Affiliation(s)
- David S. Tourigny
- Irving Institute for Cancer Dynamics, Columbia University, New York, NY, United States
- School of Mathematics, University of Birmingham, Birmingham, United Kingdom
- *Correspondence: David S. Tourigny, ; A. Ari Hakimi, ; Ritesh R. Kotecha, ; Ed Reznik,
| | - Mark Zucker
- Computational Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Minsoo Kim
- Computational Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Paul Russo
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Jonathan Coleman
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Chung-Han Lee
- Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Maria I. Carlo
- Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Ying-Bei Chen
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - A. Ari Hakimi
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States
- *Correspondence: David S. Tourigny, ; A. Ari Hakimi, ; Ritesh R. Kotecha, ; Ed Reznik,
| | - Ritesh R. Kotecha
- Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States
- *Correspondence: David S. Tourigny, ; A. Ari Hakimi, ; Ritesh R. Kotecha, ; Ed Reznik,
| | - Ed Reznik
- Computational Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, United States
- *Correspondence: David S. Tourigny, ; A. Ari Hakimi, ; Ritesh R. Kotecha, ; Ed Reznik,
| |
Collapse
|
|
43
|
Evaluation of Soluble CD90: Potential for Diagnostic Significance in Endometriosis Patients. DISEASE MARKERS 2022; 2022:9345858. [PMID: 35769819 PMCID: PMC9236764 DOI: 10.1155/2022/9345858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 06/04/2022] [Indexed: 11/25/2022]
Abstract
Background Endometriosis is a chronic and debilitating gynecologic disorder, driven by endocrine and immune dysfunctions, which lead to poor endometrial differentiation and attenuated fertility. Escape from immune surveillance and involvement of inflammatory mechanisms appear to be factors in disease progression. Current diagnostic guidelines for endometriosis still lack an efficient biomarker. Here, we report a study on two previously unexplored factors as potential biomarkers for endometriosis. Methods A case-control study was performed to evaluate the diagnostic potential of serum CD90 and CD83 levels in endometriosis patients (cases validated by surgical and histological examination) compared to healthy controls. Serum was collected from age-matched females and analyzed by ELISA. Results Comparison of endometriosis patients to the control group showed significantly elevated levels of serum CD90 (1160 ± 856 pg/mL vs. 334 ± 228 pg/mL; ∗∗∗∗p < 0.0001). A threshold value of 479.4 pg/mL was defined based on the control results, and the diagnostic efficiency of the test was estimated. The obtained sensitivity (70.4%), specificity (92.9%), positive predictive value (90.5%), and negative predictive value (76.5%) rated the test as one with promising diagnostic potential. In contrast, the analysis of serum CD83 levels showed comparable values in both groups, suggesting no association with patient status. Conclusion Elevated soluble CD90 in human serum is associated with endometriosis, which suggests its putative clinical significance as a biomarker in screening and/or diagnosis of the disease.
Collapse
|
|
44
|
Hu P, Leyton L, Hagood JS, Barker TH. Thy-1-Integrin Interactions in cis and Trans Mediate Distinctive Signaling. Front Cell Dev Biol 2022; 10:928510. [PMID: 35733855 PMCID: PMC9208718 DOI: 10.3389/fcell.2022.928510] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 05/23/2022] [Indexed: 12/04/2022] Open
Abstract
Thy-1 is a cell surface glycosylphosphatidylinositol (GPI)-anchored glycoprotein that bears a broad mosaic of biological roles across various cell types. Thy-1 displays strong physiological and pathological implications in development, cancer, immunity, and tissue fibrosis. Quite uniquely, Thy-1 is capable of mediating integrin-related signaling through direct trans- and cis-interaction with integrins. Both interaction types have shown distinctive roles, even when interacting with the same type of integrin, where binding in trans or in cis often yields divergent signaling events. In this review, we will revisit recent progress and discoveries of Thy-1–integrin interactions in trans and in cis, highlight their pathophysiological consequences and explore other potential binding partners of Thy-1 within the integrin regulation/signaling paradigm.
Collapse
Affiliation(s)
- Ping Hu
- Department of Biomedical Engineering, School of Engineering and Applied Science, University of Virginia, Charlottesville, VA, United States
| | - Lisette Leyton
- Cellular Communication Laboratory, Program of Cellular and Molecular Biology, Center for Studies on Exercise, Metabolism and Cancer (CEMC), Faculty of Medicine, Universidad de Chile, Santiago, Chile
- Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical and Pharmaceutical Sciences and Faculty of Medicine, Universidad de Chile and Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile
| | - James S. Hagood
- Department of Pediatrics, Division of Pulmonology, School of Medicine, University of North Carolina, Chapel Hill, NC, United States
- Program for Rare and Interstitial Lung Disease, School of Medicine, University of North Carolina, Chapel Hill, NC, United States
| | - Thomas H. Barker
- Department of Biomedical Engineering, School of Engineering and Applied Science, University of Virginia, Charlottesville, VA, United States
- *Correspondence: Thomas H. Barker,
| |
Collapse
|
|
45
|
Aust G, Zheng L, Quaas M. To Detach, Migrate, Adhere, and Metastasize: CD97/ADGRE5 in Cancer. Cells 2022; 11:cells11091538. [PMID: 35563846 PMCID: PMC9101421 DOI: 10.3390/cells11091538] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 04/26/2022] [Accepted: 05/02/2022] [Indexed: 11/16/2022] Open
Abstract
Tumorigenesis is a multistep process, during which cells acquire a series of mutations that lead to unrestrained cell growth and proliferation, inhibition of cell differentiation, and evasion of cell death. Growing tumors stimulate angiogenesis, providing them with nutrients and oxygen. Ultimately, tumor cells invade the surrounding tissue and metastasize; a process responsible for about 90% of cancer-related deaths. Adhesion G protein-coupled receptors (aGPCRs) modulate the cellular processes closely related to tumor cell biology, such as adhesion and detachment, migration, polarity, and guidance. Soon after first being described, individual human aGPCRs were found to be involved in tumorigenesis. Twenty-five years ago, CD97/ADGRE5 was discovered to be induced in one of the most severe tumors, dedifferentiated anaplastic thyroid carcinoma. After decades of research, the time has come to review our knowledge of the presence and function of CD97 in cancer. In summary, CD97 is obviously induced or altered in many tumor entities; this has been shown consistently in nearly one hundred published studies. However, its high expression at circulating and tumor-infiltrating immune cells renders the systemic targeting of CD97 in tumors difficult.
Collapse
Affiliation(s)
- Gabriela Aust
- Research Laboratories of the Clinic of Visceral, Transplantation, Thoracic, and Vascular Surgery, Medical School, University Hospital Leipzig, Leipzig University, 04103 Leipzig, Germany;
- Research Laboratories of the Clinic of Orthopedics, Traumatology and Plastic Surgery, Medical School, University Hospital Leipzig, Leipzig University, 04103 Leipzig, Germany;
| | - Leyu Zheng
- Research Laboratories of the Clinic of Orthopedics, Traumatology and Plastic Surgery, Medical School, University Hospital Leipzig, Leipzig University, 04103 Leipzig, Germany;
| | - Marianne Quaas
- Research Laboratories of the Clinic of Visceral, Transplantation, Thoracic, and Vascular Surgery, Medical School, University Hospital Leipzig, Leipzig University, 04103 Leipzig, Germany;
- Correspondence:
| |
Collapse
|
|
46
|
Mahmoud K, Swidan S, El-Nabarawi M, Teaima M. Lipid based nanoparticles as a novel treatment modality for hepatocellular carcinoma: a comprehensive review on targeting and recent advances. J Nanobiotechnology 2022; 20:109. [PMID: 35248080 PMCID: PMC8898455 DOI: 10.1186/s12951-022-01309-9] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Accepted: 02/12/2022] [Indexed: 12/12/2022] Open
Abstract
Liver cancer is considered one of the deadliest diseases with one of the highest disease burdens worldwide. Among the different types of liver cancer, hepatocellular carcinoma is considered to be the most common type. Multiple conventional approaches are being used in treating hepatocellular carcinoma. Focusing on drug treatment, regular agents in conventional forms fail to achieve the intended clinical outcomes. In order to improve the treatment outcomes, utilizing nanoparticles-specifically lipid based nanoparticles-are considered to be one of the most promising approaches being set in motion. Multiple forms of lipid based nanoparticles exist including liposomes, solid lipid nanoparticles, nanostructured lipid carriers, microemulsion, nanoemulsion, phytosomes, lipid coated nanoparticles, and nanoassemblies. Multiple approaches are used to enhance the tumor uptake as well tumor specificity such as intratumoral injection, passive targeting, active targeting, and stimuli responsive nanoparticles. In this review, the effect of utilizing lipidic nanoparticles is being discussed as well as the different tumor uptake enhancement techniques used.
Collapse
Affiliation(s)
- Khaled Mahmoud
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, The British University in Egypt, El-Sherouk City, Cairo, 11837, Egypt
- The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, El-Sherouk City, Cairo, 11837, Egypt
| | - Shady Swidan
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, The British University in Egypt, El-Sherouk City, Cairo, 11837, Egypt.
- The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, El-Sherouk City, Cairo, 11837, Egypt.
| | - Mohamed El-Nabarawi
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt.
| | - Mahmoud Teaima
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt
| |
Collapse
|
|
47
|
Gao R, Wang J, He X, Wang T, Zhou L, Ren Z, Yang J, Xiang X, Wen S, Yu Z, Ai H, Wang Y, Liang H, Li S, Lu Y, Zhu Y, Shi G, Chen Y. Comprehensive analysis of endoplasmic reticulum-related and secretome gene expression profiles in the progression of non-alcoholic fatty liver disease. Front Endocrinol (Lausanne) 2022; 13:967016. [PMID: 36034446 PMCID: PMC9412753 DOI: 10.3389/fendo.2022.967016] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Accepted: 07/25/2022] [Indexed: 11/13/2022] Open
Abstract
Endoplasmic reticulum (ER) is the principal organelle for protein synthesis, such as hepatokines and transmembrane proteins, and is critical for maintaining physiological function. Dysfunction of ER is associated with metabolic disorders. However, the role of ER homeostasis as well as hepatokines in the progression of non-alcoholic fatty liver disease (NAFLD) remains to be elucidated. Here we comprehensively analyzed the RNA-seq profiles of liver biopsies from 206 NAFLD patients and 10 controls from dataset GSE135251. The co-expression modules were constructed based on weighted gene co-expression network analysis and six co-expression modules were identified, of which brown module stood out to be significantly associated with fibrosis stage and NAFLD activity score (NAS). Subsequently, cytoscape with cytoHubba plugin was applied to identify hub genes in the brown module. GO and KEGG enrichment analysis of the top 20 hub genes were performed and showed the involvement of extracellular matrix formation, collagen synthesis and decomposition, etc. Further, the expression of the top 20 hub genes were found to be a consistent increasing trend as the fibrosis stages and NAS increased, which have been validated both in HFD fed and HFHC fed mice. Among these genes, THY1, PTGDS, TMPRSS3, SPON1, COL1A2, RHBDF1, COL3A1, COL5A1, COL1A1 and IGFBP7 performed well in distinguishing fibrosis stage, while COL1A2, COL3A1, THY1, RHBDF1 and COL1A2 exhibited good capacity to discriminate NAS. Besides, RHBDF1, COL3A1, QSOX1, STING1, COL5A1, IGFBP7, COL4A2, COL1A1, FKBP10 and COL1A2 also showed a strong power in the diagnosis of NAFLD. In addition, COL1A1, COL1A2, COL3A1, COL8A2, IGFBP7, PGF, PTGDS, SPON1, THY1 and TIMP1 were identified as secretome genes from the top 20 hub genes. Of them, circulated THY1 and collagen III level were validated to be significantly elevated in the MCD diet-induced mice. Thus, we provided a systemic view on understanding the pathological roles and mechanisms of ER as well as secretome in NAFLD progression. THY1, COL1A1, COL1A2, COL3A1 and RHBDF1 could be served as candidate biomarkers to evaluate the progression of NAFLD.
Collapse
Affiliation(s)
- Rong Gao
- Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jin Wang
- Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xuemin He
- Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Tongtong Wang
- Department of Clinical Immunology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Li Zhou
- Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Zhitao Ren
- Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jifeng Yang
- Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xiaoxin Xiang
- Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Shiyi Wen
- Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Zhuojun Yu
- Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Heying Ai
- Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yuchan Wang
- Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Hua Liang
- Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Shasha Li
- Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yan Lu
- Department of Clinical Immunology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yanhua Zhu
- Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Guojun Shi
- Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- *Correspondence: Yanming Chen, ; Guojun Shi,
| | - Yanming Chen
- Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- *Correspondence: Yanming Chen, ; Guojun Shi,
| |
Collapse
|
|
48
|
Poondla N, Sheykhhasan M, Akbari M, Samadi P, Kalhor N, Manoochehri H. The Promise of CAR T-Cell Therapy for the Treatment of Cancer Stem Cells: A Short Review. Curr Stem Cell Res Ther 2022; 17:400-406. [PMID: 35176990 DOI: 10.2174/1574888x17666220217101817] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 10/27/2021] [Accepted: 11/15/2021] [Indexed: 11/22/2022]
Abstract
Chimeric antigen receptor (CAR) T-cell therapy is a type of sophisticated tailored immunotherapy used to treat a variety of tumors. Immunotherapy works by utilizing the body's own immune system to discover and destroy malignant cells. In CAR-T therapy, a patient's own immune cells are genetically engineered to recognize and attack cancer. Treatments employing CAR T-cells are currently showing promising therapeutic results in patients with hematologic malignancies, and their safety and feasibility in solid tumors have been verified. In this review, we will discuss in detail the likelihood that CAR Tcells inhibit cancer stem cells (CSCs) by selectively targeting their cell surface markers will ultimately improve the therapeutic response for patients with various forms of cancer. This review addresses the major components of cancer stem cell (CSC)-targeted CAR T-cells against malignancies, from bench to bedside.
Collapse
Affiliation(s)
- Naresh Poondla
- Richmond University Medical Center, 355, Bard Avenue, Staten Island, New York 10310, United States
| | - Mohsen Sheykhhasan
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
- Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research (ACECR), Qom Branch, Iran
| | - Mohammad Akbari
- Department of Medical School, Faculty of Medical Sciences, Islamic Azad University, Tonekabon Branch, Mazandaran, Iran
| | - Pouria Samadi
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Naser Kalhor
- Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research (ACECR), Qom Branch, Iran
| | - Hamed Manoochehri
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| |
Collapse
|
|
49
|
Guo K, Xiao N, Liu Y, Wang Z, Tóth J, Gyenis J, Thakur VK, Oyane A, Shubhra QT. Engineering polymer nanoparticles using cell membrane coating technology and their application in cancer treatments: Opportunities and challenges. NANO MATERIALS SCIENCE 2021. [DOI: 10.1016/j.nanoms.2021.12.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
|
|
50
|
Jugniot N, Bam R, Paulmurugan R. Expression and purification of a native Thy1-single-chain variable fragment for use in molecular imaging. Sci Rep 2021; 11:23026. [PMID: 34845270 PMCID: PMC8630227 DOI: 10.1038/s41598-021-02445-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 11/16/2021] [Indexed: 11/23/2022] Open
Abstract
Molecular imaging using singlechain variable fragments (scFv) of antibodies targeting cancer specific antigens have been considered a non-immunogenic approach for early diagnosis in the clinic. Usually, production of proteins is performed within Escherichia coli. Recombinant proteins are either expressed in E. coli cytoplasm as insoluble inclusion bodies, that often need cumbersome denaturation and refolding processes, or secreted toward the periplasm as soluble proteins that highly reduce the overall yield. However, production of active scFvs in their native form, without any heterologous fusion, is required for clinical applications. In this study, we expressed an anti-thymocyte differentiation antigen-scFv (Thy1-scFv) as a fusion protein with a N-terminal sequence including 3 × hexa-histidines, as purification tags, together with a Trx-tag and a S-tag for enhanced-solubility. Our strategy allowed to recover ~ 35% of Thy1-scFv in the soluble cytoplasmic fraction. An enterokinase cleavage site in between Thy1-scFv and the upstream tags was used to regenerate the protein with 97.7 ± 2.3% purity without any tags. Thy1-scFv showed functionality towards its target on flow cytometry assays. Finally, in vivo molecular imaging using Thy1-scFv conjugated to an ultrasound contrast agent (MBThy1-scFv) demonstrated signal enhancement on a transgenic pancreatic ductal adenocarcinoma (PDAC) mouse model (3.1 ± 1.2 a.u.) compared to non-targeted control (0.4 ± 0.4 a.u.) suggesting potential for PDAC early diagnosis. Overall, our strategy facilitates the expression and purification of Thy1-scFv while introducing its ability for diagnostic molecular imaging of pancreatic cancer. The presented methodology could be expanded to other important eukaryotic proteins for various applications, including but not limited to molecular imaging.
Collapse
Affiliation(s)
- Natacha Jugniot
- Department of Radiology, Molecular Imaging Program at Stanford (MIPS), Canary Center for Cancer Early Detection at Stanford, Stanford University School of Medicine, Stanford University, 3155 Porter Drive, Palo Alto, CA, 94304, USA
| | - Rakesh Bam
- Department of Radiology, Molecular Imaging Program at Stanford (MIPS), Canary Center for Cancer Early Detection at Stanford, Stanford University School of Medicine, Stanford University, 3155 Porter Drive, Palo Alto, CA, 94304, USA
| | - Ramasamy Paulmurugan
- Department of Radiology, Molecular Imaging Program at Stanford (MIPS), Canary Center for Cancer Early Detection at Stanford, Stanford University School of Medicine, Stanford University, 3155 Porter Drive, Palo Alto, CA, 94304, USA.
| |
Collapse
|