GO:1902461 negative regulation of mesenchymal stem cell proliferation: Signaling Pathways, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1902461 describes any process that stops, prevents, or reduces the frequency, rate, or extent of mesenchymal stem cell (MSC) proliferation.
• MSC proliferation is negatively regulated by paracrine factors, exosomal microRNAs, and intracellular signaling pathways such as Wnt/β-catenin and Smad [1,2,3].
• Dysregulation of this process contributes to fibrosis, impaired bone regeneration, and cancer progression [1,2,3].
• Key molecular players include Foxf1, miR-192-5p, miR-7-5p, and IL-17RA, which modulate MSC proliferation in disease contexts [1,2,3].
• CRISPR-based knockout, knock-in, and overexpression models are essential to dissect the causal roles of these regulators [2,3].
• Understanding GO:1902461 provides therapeutic targets for regenerative medicine and cancer therapy [1,2,3].
Description
Mesenchymal stem cells (MSCs) are multipotent stromal cells that can self-renew and differentiate into multiple lineages, and their proliferation must be tightly controlled to maintain tissue homeostasis. The Gene Ontology term GO:1902461, negative regulation of mesenchymal stem cell proliferation, encompasses any process that stops, prevents, or reduces the frequency, rate, or extent of MSC proliferation. This regulation is critical in development, tissue repair, and disease; for example, exosomes from human adipose MSCs attenuate hypertrophic scar fibrosis by delivering miR-192-5p, which targets IL-17RA and modulates the Smad axis, thereby influencing MSC proliferation. Similarly, Foxf1 knockdown promotes bone marrow MSC osteogenesis and prevents ovariectomy-induced bone loss by activating Wnt/β-catenin signaling, highlighting the interplay between proliferation and differentiation. In acute myeloid leukemia, bone MSC-derived exosomal miR-7-5p inhibits leukemia progression by targeting OSBPL11, illustrating how negative regulation of MSC proliferation can impact cancer. Thus, deciphering the mechanisms of GO:1902461 is essential for developing targeted therapies in regenerative medicine and oncology.
negative regulation of mesenchymal stem cell proliferation At A Glance
| GO ID | GO:1902461 |
|---|---|
| GO term | negative regulation of mesenchymal stem cell proliferation |
| Ontology | biological_process |
| Synonym | inhibition of MSC proliferation; downregulation of mesenchymal stem cell proliferation |
| Major function | Inhibits the self-renewal and expansion of mesenchymal stem cells |
| Related processes | MSC differentiation, osteogenesis, fibrosis, cancer progression |
| Key regulators | Foxf1, miR-192-5p, miR-7-5p, IL-17RA, Wnt/β-catenin |
| Disease relevance | Hypertrophic scar, osteoporosis, acute myeloid leukemia |
What Is GO:1902461?
GO:1902461 is a biological process term defined as any process that stops, prevents, or reduces the frequency, rate, or extent of mesenchymal stem cell proliferation. It includes signaling events, transcriptional changes, and extracellular cues that inhibit the self-renewal division of MSCs.
Why Is negative regulation of mesenchymal stem cell proliferation Important in Cell Biology?
Negative regulation of MSC proliferation is vital for balancing tissue regeneration and preventing pathological overgrowth. Dysregulation can lead to fibrosis, impaired bone healing, or support tumor progression, making it a key area for therapeutic intervention [1,2,3].
• Controls MSC self-renewal to prevent exhaustion or tumorigenic transformation.
• Modulates wound healing and scar formation, as shown by exosomal miR-192-5p in hypertrophic scars.
• Influences bone homeostasis; Foxf1 knockdown enhances osteogenesis and prevents bone loss.
• Affects cancer progression; MSC-derived exosomal miR-7-5p inhibits acute myeloid leukemia.
• Regulates immune responses via MSC-derived exosomes in Sjögren's syndrome.
• Plays a role in osteoarthritis through circHIPK3/miR-124-3p/MYH9 axis.
• Impacts melanoma survival via MSC exosomes and miR-138-5p/SOX4 pathway.
• Involved in Leydig cell stem cell proliferation and differentiation.
• Autophagy modulates MSC proliferation in skin wound healing.
• Provides targets for CRISPR-based screens to identify novel regulators [2,3].
What Happens During negative regulation of mesenchymal stem cell proliferation?
Extracellular signals and exosomal microRNAs
In simple terms: Cells receive messages from outside that tell them to stop dividing.
Exosomes derived from human adipose MSCs deliver miR-192-5p to target cells, where it downregulates IL-17RA and modulates the Smad axis, leading to reduced MSC proliferation in hypertrophic scar fibrosis. Similarly, bone MSC-derived exosomal miR-7-5p targets OSBPL11 to inhibit acute myeloid leukemia progression, indirectly affecting MSC proliferation.
Intracellular signaling pathways
In simple terms: Inside the cell, specific pathways act as brakes on division.
Foxf1 knockdown activates the Wnt/β-catenin signaling pathway, which promotes osteogenesis and prevents ovariectomy-induced bone loss, partly by negatively regulating MSC proliferation. The circHIPK3/miR-124-3p/MYH9 axis in MSC-derived extracellular vesicles prevents osteoarthritis development, involving negative regulation of MSC proliferation.
Transcriptional and post-transcriptional control
In simple terms: Genes and microRNAs control the production of proteins that stop cell division.
miR-138-5p from human MSC-derived exosomes modulates the SOX4 pathway to inhibit melanoma cell survival, which may involve negative regulation of MSC proliferation. Autophagy-related processes also influence MSC proliferation during skin wound healing.
Immune modulation and niche interactions
In simple terms: MSCs interact with immune cells, and this crosstalk can slow their growth.
Umbilical MSC-derived exosomes have immunomodulatory effects on CD4+ T cells in primary Sjögren's syndrome, potentially affecting MSC proliferation. Leydig cell stem cells, which share some properties with MSCs, undergo regulated proliferation and differentiation.
Key Genes Involved in GO:1902461 negative regulation of mesenchymal stem cell proliferation
The following genes and non-coding RNAs have been implicated in the negative regulation of mesenchymal stem cell proliferation.
| Gene | Major Role | Research Relevance |
|---|---|---|
| Foxf1 | Transcription factor; knockdown activates Wnt/β-catenin | Promotes osteogenesis and prevents bone loss |
| IL-17RA | Receptor for IL-17; target of miR-192-5p | Mediates hypertrophic scar fibrosis |
| OSBPL11 | Oxysterol-binding protein; target of miR-7-5p | Inhibits acute myeloid leukemia progression |
| MYH9 | Non-muscle myosin heavy chain; regulated by circHIPK3/miR-124-3p | Prevents osteoarthritis development |
| SOX4 | Transcription factor; modulated by miR-138-5p | Inhibits melanoma survival |
| miR-192-5p | MicroRNA in adipose MSC exosomes | Attenuates hypertrophic scar fibrosis |
| miR-7-5p | MicroRNA in bone MSC exosomes | Inhibits acute myeloid leukemia |
| miR-124-3p | MicroRNA regulated by circHIPK3 | Prevents osteoarthritis |
| miR-138-5p | MicroRNA in MSC exosomes | Inhibits melanoma survival |
| circHIPK3 | Circular RNA; sponge for miR-124-3p | Prevents osteoarthritis |
| Smad | Signaling effector downstream of IL-17RA | Modulates fibrosis |
| Wnt/β-catenin | Signaling pathway | Regulates osteogenesis and bone loss |
| Autophagy-related genes | Cellular degradation pathway | Influences skin wound healing |
| CD4+ T cells | Immune cells modulated by MSC exosomes | Sjögren's syndrome |
| Leydig cell stem cells | Stem cells in testis | Proliferation and differentiation |
How Is negative regulation of mesenchymal stem cell proliferation Regulated?
Negative regulation of MSC proliferation is controlled by a network of extracellular cues, exosomal microRNAs, and intracellular signaling pathways. For instance, miR-192-5p from adipose MSC exosomes targets IL-17RA and modulates Smad signaling to reduce fibrosis. Foxf1 knockdown activates Wnt/β-catenin, shifting MSCs toward osteogenesis and away from proliferation. Exosomal miR-7-5p from bone MSCs targets OSBPL11 to inhibit leukemia progression. Autophagy also plays a role in skin wound healing by affecting MSC proliferation. These regulatory mechanisms are context-dependent and involve cross-talk between immune cells and MSCs.
negative regulation of mesenchymal stem cell proliferation and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| IL-17RA | Hypertrophic scar fibrosis | Knockout in adipose MSCs; exosome delivery |
| Foxf1 | Osteoporosis | Knockdown in bone marrow MSCs; ovariectomy mouse model |
| OSBPL11 | Acute myeloid leukemia | Knockout in bone MSCs; leukemia xenograft |
| MYH9 | Osteoarthritis | Knock-in of circHIPK3; chondrocyte co-culture |
| SOX4 | Melanoma | Overexpression in melanoma cells; MSC exosome treatment |
Hypertrophic Scar Fibrosis
Exosomes from human adipose MSCs attenuate hypertrophic scar fibrosis by delivering miR-192-5p, which downregulates IL-17RA and modulates the Smad axis, leading to negative regulation of MSC proliferation and reduced fibrosis.
Osteoporosis and Bone Loss
Foxf1 knockdown promotes bone marrow MSC osteogenesis and prevents ovariectomy-induced bone loss by activating Wnt/β-catenin signaling, which involves negative regulation of MSC proliferation.
Acute Myeloid Leukemia
Bone MSC-derived exosomal miR-7-5p inhibits acute myeloid leukemia progression by targeting OSBPL11, highlighting the role of negative regulation of MSC proliferation in cancer.
Osteoarthritis
MSC-derived extracellular vesicles prevent osteoarthritis development via the circHIPK3/miR-124-3p/MYH9 axis, which includes negative regulation of MSC proliferation.
From negative regulation of mesenchymal stem cell proliferation-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does Foxf1 knockdown inhibit MSC proliferation? | CRISPR knockout of Foxf1 in bone marrow MSCs |
| Can miR-192-5p mimic reduce fibrosis? | Overexpression of miR-192-5p in adipose MSCs; exosome isolation |
| Is OSBPL11 required for leukemia progression? | CRISPR knockout of OSBPL11 in bone MSCs; AML xenograft |
| Does circHIPK3 sponge miR-124-3p? | Knock-in of circHIPK3 in MSCs; luciferase reporter |
| What is the role of SOX4 in melanoma? | Point mutation of SOX4 in melanoma cells; MSC exosome treatment |
| How does autophagy affect MSC proliferation? | Knockout of autophagy genes in MSCs; wound healing assay |
How to Study the negative regulation of mesenchymal stem cell proliferation Process
| Method | What It Measures | Typical Application |
|---|---|---|
| CRISPR knockout | Gene function loss | Identify regulators of MSC proliferation [2,3] |
| Exosome isolation | Extracellular vesicle cargo | miRNA delivery to target cells [1,3,5] |
| EdU assay | DNA synthesis | Quantify MSC proliferation [1,2] |
| RNA-seq | Transcriptome changes | Identify pathways altered by miR-192-5p |
| Western blot | Protein expression | Validate IL-17RA, Smad, β-catenin [1,2] |
| Luciferase reporter | miRNA-target interaction | Confirm miR-124-3p binding to circHIPK3 |
| Xenograft | Tumor growth | Test OSBPL11 knockout in AML |
| Ovariectomy model | Bone loss | Evaluate Foxf1 knockdown |
CRISPR Screening
Genome-wide CRISPR knockout screens can identify novel regulators of MSC proliferation. For example, targeting Foxf1, OSBPL11, and MYH9 in MSCs followed by proliferation assays reveals their roles [2,3,7].
Exosome Isolation and Characterization
Exosomes from MSCs can be isolated by ultracentrifugation and characterized by nanoparticle tracking, Western blot for CD9/CD63, and electron microscopy. Their miRNA cargo can be profiled by RNA-seq [1,3,5].
Proliferation Assays
MSC proliferation is measured by EdU incorporation, MTT, or CFSE dilution. These assays are used to validate the effects of genetic manipulations or exosome treatments [1,2,3].
In Vivo Disease Models
Ovariectomy-induced bone loss, hypertrophic scar, and leukemia xenograft models are used to study the impact of negative regulation of MSC proliferation in vivo [1,2,3].
How CRISPR Can Be Used to Study GO:1902461 negative regulation of mesenchymal stem cell proliferation
Knockout
CRISPR knockout of Foxf1 in bone marrow MSCs activates Wnt/β-catenin and prevents bone loss, demonstrating its role in negative regulation of MSC proliferation. Similarly, OSBPL11 knockout in bone MSCs can be used to study leukemia progression.
Point Mutation
Point mutations in SOX4 can be introduced to dissect its role in melanoma survival and MSC proliferation. Such models help identify phosphorylation sites or DNA-binding residues critical for function.
Knock-in
Knock-in of circHIPK3 or miR-124-3p into MSCs allows precise control of their expression to study osteoarthritis development. Tagged knock-in of Foxf1 can track its localization and interactions.
Overexpression
Overexpression of miR-192-5p in adipose MSCs enhances exosomal delivery and reduces hypertrophic scar fibrosis by targeting IL-17RA. Overexpression of miR-7-5p in bone MSCs inhibits AML progression.
How EDITGENE Supports negative regulation of mesenchymal stem cell proliferation Research
Researchers studying negative regulation of mesenchymal stem cell proliferation-related genes often need to determine whether a candidate gene is causally involved in MSC quiescence, differentiation, or disease progression. EDITGENE provides end-to-end CRISPR solutions to accelerate this discovery.
Contact EDITGENE today to design your custom CRISPR model for negative regulation of mesenchymal stem cell proliferation research.
Frequently Asked Questions About negative regulation of mesenchymal stem cell proliferation
What is GO:1902461?
GO:1902461 is the Gene Ontology term for negative regulation of mesenchymal stem cell proliferation, describing any process that stops or reduces MSC proliferation.
What genes are involved in negative regulation of mesenchymal stem cell proliferation?
Key genes include Foxf1, IL-17RA, OSBPL11, MYH9, and SOX4, as well as microRNAs like miR-192-5p and miR-7-5p [1,2,3,7,8].
How do exosomes regulate MSC proliferation?
MSC-derived exosomes carry microRNAs such as miR-192-5p and miR-7-5p that target mRNAs like IL-17RA and OSBPL11, leading to reduced MSC proliferation [1,3].
What diseases are associated with dysregulation of MSC proliferation?
Hypertrophic scar fibrosis, osteoporosis, acute myeloid leukemia, and osteoarthritis are linked to altered negative regulation of MSC proliferation [1,2,3,7].
How can CRISPR be used to study negative regulation of MSC proliferation?
CRISPR knockout, knock-in, and overexpression models allow functional validation of genes like Foxf1 and OSBPL11 in MSC proliferation assays [2,3].
What is the role of Foxf1 in MSC proliferation?
Foxf1 knockdown activates Wnt/β-catenin signaling, promoting osteogenesis and preventing bone loss, partly by negatively regulating MSC proliferation.
Which microRNAs inhibit MSC proliferation?
miR-192-5p, miR-7-5p, miR-124-3p, and miR-138-5p have been shown to negatively regulate MSC proliferation in various contexts [1,3,7,8].
How does autophagy affect MSC proliferation?
Autophagy modulates MSC proliferation during skin wound healing, though the exact mechanisms are still being elucidated.
What are the research methods to study GO:1902461?
Common methods include CRISPR screening, exosome isolation, proliferation assays (EdU, MTT), RNA-seq, and in vivo disease models [1,2,3].
Can negative regulation of MSC proliferation be targeted therapeutically?
Yes, modulating this process with exosomal microRNAs or CRISPR-based gene editing holds promise for treating fibrosis, bone loss, and cancer [1,2,3].
Conclusion
GO:1902461, negative regulation of mesenchymal stem cell proliferation, is a critical biological process that maintains tissue homeostasis and prevents disease. Research has identified key regulators such as Foxf1, miR-192-5p, and miR-7-5p, which operate through exosomal and signaling pathways [1,2,3]. Understanding these mechanisms offers therapeutic opportunities for fibrosis, osteoporosis, and cancer. EDITGENE provides comprehensive CRISPR solutions to accelerate discovery in this field.
References
- 1. Li Y et al.. 2021. Exosomes derived from human adipose mesenchymal stem cells attenuate hypertrophic scar fibrosis by miR-192-5p/IL-17RA/Smad axis.. Stem Cell Res Ther 12(1):221 PMID: 33789737
- 2. Shen G et al.. 2020. Foxf1 knockdown promotes BMSC osteogenesis in part by activating the Wnt/β-catenin signalling pathway and prevents ovariectomy-induced bone loss.. EBioMedicine 52:102626 PMID: 31981979
- 3. Jiang D et al.. 2022. Bone mesenchymal stem cell-derived exosomal microRNA-7-5p inhibits progression of acute myeloid leukemia by targeting OSBPL11.. J Nanobiotechnology 20(1):29 PMID: 35012554
- 4. Ren H et al.. 2022. Autophagy and skin wound healing.. Burns Trauma 10:tkac003 PMID: 35187180
- 5. Ma D et al.. 2023. Immunomodulatory effects of umbilical mesenchymal stem cell-derived exosomes on CD4(+) T cells in patients with primary Sjögren's syndrome.. Inflammopharmacology 31(4):1823-1838 PMID: 37012581
- 6. Chen H et al.. 2017. Leydig cell stem cells: Identification, proliferation and differentiation.. Mol Cell Endocrinol 445:65-73 PMID: 27743991
- 7. Li S et al.. 2021. Mesenchymal stem cell-derived extracellular vesicles prevent the development of osteoarthritis via the circHIPK3/miR-124-3p/MYH9 axis.. J Nanobiotechnology 19(1):194 PMID: 34193158
- 8. Wang X et al.. 2022. Human mesenchymal stem cell derived exosomes inhibit the survival of human melanoma cells through modulating miR-138-5p/SOX4 pathway.. Cancer Biomark 34(4):533-543 PMID: 35275523
