Regular ArticleStructure and Chromosomal Localization of the Human Stromal Cell-Derived Factor 1 (SDF1) Gene
Abstract
Stromal cell-derived factors 1α and 1β are small cytokines belonging to the intercrine CXC subfamily and originally isolated from a murine bone-marrow stroma cell line by the signal sequence trap method. cDNA and genomic clones of human SDF1α and SDF1β (SDF1A and SDF1B) were isolated and characterized. cDNAs of SDF1α and SDF1β encode proteins of 89 and 93 amino acids, respectively. SDF1α and SDF1β sequences are more than 92% identical to those of the human counterparts. The genomic structure of the SDF1 gene revealed that human SDF1α and SDF1β are encoded by a single gene and arise by alternative splicing. SDF1α and SDF1β are encoded by 3 and 4 exons, respectively. Ubiquitous expression of the SDF1 gene, except in blood cells, was consistent with the presence of the GC-rich sequence in the 5′-flanking region of the SDF1 gene, as is often the case in the "housekeeping" genes. Although genes encoding other members of the intercrine family are localized on chromosome 4q or 17q, the human SDF1 gene was mapped to chromosome 10q by fluorescence in situ hybridization. Strong evolutionary conservation and unique chromosomal localization of the SDF1 gene suggest that SDF1α and SDF1β may have important functions distinct from those of other members of the intercrine family.
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An emerging paradigm of CXCL12 involvement in the metastatic cascade
2024, Cytokine and Growth Factor ReviewsThe chemokine CXCL12, also known as stromal cell-derived factor 1 (SDF1), has emerged as a pivotal regulator in the intricate molecular networks driving cancer progression. As an influential factor in the tumor microenvironment, CXCL12 plays a multifaceted role that spans beyond its traditional role as a chemokine inducing invasion and metastasis. Indeed, CXCL12 has been assigned functions related to epithelial-to-mesenchymal transition, cancer cell stemness, angiogenesis, and immunosuppression, all of which are currently viewed as specialized biological programs contributing to the “metastatic cascade” among other cancer hallmarks. Its interaction with its cognate receptor, CXCR4, initiates a cascade of events that not only shapes the metastatic potential of tumor cells but also defines the niches within the secondary organs that support metastatic colonization. Given the profound implications of CXCL12 in the metastatic cascade, understanding its mechanistic underpinnings is of paramount importance for the targeted elimination of rate-limiting steps in the metastatic process. This review aims to provide a comprehensive overview of the current knowledge surrounding the role of CXCL12 in cancer metastasis, especially its molecular interactions rationalizing its potential as a therapeutic target.
WHIM syndrome is an autosomal dominant immunodeficiency disorder caused by gain-of-function mutations in chemokine receptor CXCR4 that promote severe panleukopenia because of retention of mature leukocytes in the bone marrow (BM). We previously reported that Cxcr4-haploinsufficient (Cxcr4+/o) hematopoietic stem cells (HSCs) have a strong selective advantage for durable hematopoietic reconstitution over wild-type (Cxcr4+/+) and WHIM (Cxcr4+/w) HSCs and that a patient with WHIM was spontaneously cured by chromothriptic deletion of the disease allele in an HSC, suggesting that WHIM allele inactivation through gene editing may be a safe genetic cure strategy for the disease. We have developed a 2-step preclinical protocol of autologous hematopoietic stem and progenitor cell (HSPC) transplantation to achieve this goal. First, 1 copy of Cxcr4 in HSPCs was inactivated in vitro by CRISPR/Cas9 editing with a single guide RNA (sgRNA) that does not discriminate between Cxcr4+/w and Cxcr4+/+ alleles. Then, through in vivo natural selection, WHIM allele–inactivated cells were enriched over wild-type allele–inactivated cells. The WHIM allele–inactivated HSCs retained long-term pluripotency and selective hematopoietic reconstitution advantages. To our knowledge, this is the first example of gene therapy for an autosomal dominant gain-of-function disease using a disease allele inactivation strategy in place of the less efficient disease allele repair approach.
Novel characterization of CXCR4 expressing cells in uninfected and herpes simplex virus-1 infected corneas
2023, Ocular SurfaceTo characterize CXCR4-expressing cells in uninfected and herpes simplex virus-1 (HSV-1) infected corneas.
The corneas of C57BL/6J mice were infected with HSV-1 McKrae. The RT-qPCR assay detected CXCR4 and CXCL12 transcripts in uninfected and HSV-1-infected corneas. Immunofluorescence staining for CXCR4 and CXCL12 protein was performed in the frozen sections of herpes stromal keratitis (HSK) corneas. Flow cytometry assay characterized the CXCR4-expressing cells in uninfected and HSV-1-infected corneas.
Flow cytometry data showed CXCR4 expressing cells in the separated epithelium and stroma of uninfected corneas. In the uninfected stroma, CD11b + F4/80+ macrophages are the predominant CXCR4-expressing cells. In contrast, most CXCR4 expressing cells in the uninfected epithelium were CD207 (langerin)+, CD11c+, and expressed MHC class II molecule, documenting the Langerhans cells (LCs) phenotype. After corneal HSV-1 infection, CXCR4 and CXCL12 mRNA levels increased significantly in HSK corneas than in uninfected corneas. Immunofluorescence staining showed CXCR4 and CXCL12 protein localization in the newly formed blood vessels in the HSK cornea. Furthermore, the infection resulted in LCs proliferation, causing an increase in their numbers in the epithelium at 4 days post-infection (p.i.). However, by 9-day p.i., the LCs numbers declined to the counts observed in naïve corneal epithelium. Our results also showed neutrophils and vascular endothelial cells as the prominent CXCR4-expressing cell types in the stroma of HSK corneas.
Together, our data demonstrate the expression of CXCR4 on resident antigen presenting cells in the uninfected cornea and on infiltrating neutrophils and newly formed blood vessels in the HSK cornea.
CXCR4 mediates the effects of IGF-1R signaling in rodent bone homeostasis and fracture repair
2023, BoneNon-union fractures have considerable clinical and economic burdens and yet the underlying pathogenesis remains largely undetermined. The fracture healing process involves cellular differentiation, callus formation and remodeling, and implies the recruitment and differentiation of mesenchymal stem cells that are not fully characterized. C-X-C chemokine receptor 4 (CXCR4) and Insulin-like growth factor 1 receptor (IGF-1R) are expressed in the fracture callus, but their interactions still remain elusive. We hypothesized that the regulation of CXCR4 by IGF-1R signaling is essential to maintain the bone homeostasis and to promote fracture repair. By using a combination of in vivo and in vitro approaches, we found that conditional ablation of IGF-1R in osteochondroprogenitors led to defects in bone formation and mineralization that associated with altered expression of CXCR4 by a discrete population of endosteal cells. These defects were corrected by AMD3100 (a CXCR4 antagonist). Furthermore, we found that the inducible ablation of IGF-1R in osteochondroprogenitors led to fracture healing failure, that associated with an altered expression of CXCR4. In vivo AMD3100 treatment improved fracture healing and normalized CXCR4 expression. Moreover, we determined that these effects were mediated through the IGF-1R/Insulin receptor substrate 1 (IRS-1) signaling pathway. Taken together, our studies identified a novel population of endosteal cells that is functionally regulated through the modulation of CXCR4 by IGF-1R signaling, and such control is essential in bone homeostasis and fracture healing. Knowledge gained from these studies has the potential to accelerate the development of novel therapeutic interventions by targeting CXCR4 signaling to treat non-unions.
Evolution of developmental and comparative immunology in poultry: The regulators and the regulated
2023, Developmental and Comparative ImmunologyAvian has a unique immune system that evolved in response to environmental pressures in all aspects of innate and adaptive immune responses, including localized and circulating lymphocytes, diversity of immunoglobulin repertoire, and various cytokines and chemokines. All of these attributes make birds an indispensable vertebrate model for studying the fundamental immunological concepts and comparative immunology. However, research on the immune system in birds lags far behind that of humans, mice, and other agricultural animal species, and limited immune tools have hindered the adequate application of birds as disease models for mammalian systems. An in-depth understanding of the avian immune system relies on the detailed studies of various regulated and regulatory mediators, such as cell surface antigens, cytokines, and chemokines. Here, we review current knowledge centered on the roles of avian cell surface antigens, cytokines, chemokines, and beyond. Moreover, we provide an update on recent progress in this rapidly developing field of study with respect to the availability of immune reagents that will facilitate the study of regulatory and regulated components of poultry immunity. The new information on avian immunity and available immune tools will benefit avian researchers and evolutionary biologists in conducting fundamental and applied research.
Decreased serum CXCL12/SDF-1 concentrations may reflect disease severity of non-traumatic osteonecrosis of femoral head
2022, Clinica Chimica ActaThe current study was performed to investigate the potential association of serum CXCL12 with disease severity in non-traumatic ONFH.
This study enrolled 182 patients with non-traumatic ONFH and 182 age- and gender-matched healthy controls. The CXCL12 levels in serum were measured by enzyme-linked immunosorbent assay. Meanwhile, serum levels of procollagen type I (PINP) and Interleukin-33(IL-33) were also detected. The radiographic severity was determined by FICAT grade. Clinical severity was evaluated by visual analogue scale (VAS), Harris Hip Score (HHS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Among the non-traumatic ONFH, 90 patients ONFH received total hip arthroplasty, the localization and expression of the CXCL12 protein and mRNA were detected by immunohistochemistry, Western blot analysis, RT-PCR and in necrotic area and adjacent non-necrotic area from lesioned femoral neck from ONFH patients and healthy femoral head from femoral neck fracture patients. Receiver operating characteristic (ROC) curve analysis was carried out to confirm the diagnostic value serum CXCL12, PINP and IL-33 with regard to the FICAT grade.
Serum CXCL12 levels were significantly lower in non-traumatic ONFH patients compared with healthy controls. CXCL12 mRNA and protein expressions were both significantly decreased in necrotic area in comparison with non-necrotic area and healthy femoral head. Serum CXCL12 concentrations were drastically reduced in patients with FICAT stage 4 compared with stage 3, and CXCL12 concentrations in patients with stage 3 were markedly lower than stage 2. Serum CXCL12 levels were negatively related to FICAT grading. In addition, Serum CXCL12 concentrations were also negatively related to VAS, WOMAC scores and positively correlated with HHS scores. Meanwhile, serum CXCL12 levels were positively correlated with serum PINP and negatively correlated with IL-33 levels. ROC curve analysis implicated that decrease CXCL12 in serum may act as a favorable marker for FICAT grade.
Decreased serum CXCL12 concentrations may reflect disease severity of non-traumatic ONFH.