Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 2 de 2
Filter
Add more filters










Database
Language
Publication year range
1.
Dev Cell ; 59(12): 1506-1522.e11, 2024 Jun 17.
Article in English | MEDLINE | ID: mdl-38582082

ABSTRACT

The commitment and differentiation of human placental progenitor cytotrophoblast (CT) cells are crucial for a successful pregnancy, but the underlying mechanism remains poorly understood. Here, we identified the transcription factor (TF), specificity protein 6 (SP6), as a human species-specific trophoblast lineage TF expressed in human placental CT cells. Using pluripotent stem cells as a model, we demonstrated that SP6 controls CT generation and the establishment of trophoblast stem cells (TSCs) and identified msh homeobox 2 (MSX2) as the downstream effector in these events. Mechanistically, we showed that SP6 interacts with histone acetyltransferase P300 to alter the landscape of H3K27ac at targeted regulatory elements, thereby favoring transcriptional activation and facilitating CT cell fate decisions and TSC maintenance. Our results established SP6 as a regulator of the human trophoblast lineage and implied its role in placental development and the pathogenies of placental diseases.


Subject(s)
Cell Differentiation , Homeodomain Proteins , Trophoblasts , Humans , Trophoblasts/metabolism , Trophoblasts/cytology , Female , Homeodomain Proteins/metabolism , Homeodomain Proteins/genetics , Pregnancy , Placenta/metabolism , Placenta/cytology , Cell Lineage , Placentation , Transcription Factors/metabolism , Transcription Factors/genetics , Stem Cells/metabolism , Stem Cells/cytology , Regulatory Sequences, Nucleic Acid/genetics , Pluripotent Stem Cells/metabolism , Pluripotent Stem Cells/cytology
2.
Blood ; 141(26): 3184-3198, 2023 06 29.
Article in English | MEDLINE | ID: mdl-37001042

ABSTRACT

The bone marrow microenvironment supports leukocyte mobilization and differentiation and controls the development of leukemias, including acute myeloid leukemia (AML). Here, we found that the development of AML xenotransplants was suppressed in mice with osteoclasts tuberous sclerosis 1 (Tsc1) deletion. Tsc1-deficient osteoclasts released a high level of interleukin-34 (IL-34), which efficiently induced AML cell differentiation and prevented AML progression in various preclinical models. Conversely, AML development was accelerated in mice deficient in IL-34. Interestingly, IL-34 inhibited AML independent of its known receptors but bound directly to triggering receptor expressed on myeloid cells 2 (TREM2), a key hub of immune signals. TREM2-deficient AML cells and normal myeloid cells were resistant to IL-34 treatment. Mechanistically, IL-34-TREM2 binding rapidly phosphorylated Ras protein activator like 3 and inactivated extracellular signal-regulated protein kinase 1/2 signaling to prevent AML cell proliferation and stimulate differentiation. Furthermore, TREM2 was downregulated in patients with AML and associated with a poor prognosis. This study identified TREM2 as a novel receptor for IL-34, indicating a promising strategy for overcoming AML differentiation blockade in patients with AML.


Subject(s)
Leukemia, Myeloid, Acute , Animals , Mice , Bone Marrow/metabolism , Carrier Proteins/metabolism , Interleukins/genetics , Interleukins/metabolism , Leukemia, Myeloid, Acute/metabolism , Signal Transduction , Tumor Microenvironment
SELECTION OF CITATIONS
SEARCH DETAIL
...