GO:0072201 negative regulation of mesenchymal cell proliferation: Signaling Mechanisms, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0072201 describes any biological process that decreases the frequency, rate or extent of mesenchymal cell proliferation, where mesenchymal cells are loosely organized cells that give rise to three-dimensional tissues.
• Key signaling pathways controlling this process include Wnt/β-catenin, PI3K/AKT, and Smad-dependent TGF-β signaling, which are frequently modulated by microRNAs and extracellular vesicles.
• Dysregulation of negative regulation of mesenchymal cell proliferation contributes to hypertrophic scar fibrosis, impaired fracture healing, and abnormal osteogenesis.
• Mesenchymal stem cell (MSC)-derived exosomes carrying microRNAs such as miR-192-5p, miR-26a-5p, and miR-29b-3p can suppress mesenchymal cell proliferation and influence tissue repair.
• FOXF1 knockdown promotes bone marrow mesenchymal stem cell osteogenesis by activating Wnt/β-catenin signaling, highlighting a critical inhibitory node in mesenchymal proliferation.
• CRISPR-based knockout, knock-in, and overexpression models are essential for dissecting the causal roles of specific genes in negative regulation of mesenchymal cell proliferation.
Description
Mesenchymal cells are loosely organized, undifferentiated cells that give rise to connective tissues, bone, cartilage, and other three-dimensional structures. The precise control of their proliferation is fundamental for embryonic development, tissue homeostasis, and repair. GO:0072201, negative regulation of mesenchymal cell proliferation, refers to any process that decreases the frequency, rate, or extent of mesenchymal cell proliferation. This biological process is critical for preventing excessive cell expansion that can lead to fibrosis, tumor stroma formation, or impaired tissue regeneration. Understanding the molecular players that restrain mesenchymal cell proliferation is therefore of broad interest in developmental biology, cancer research, and regenerative medicine. Recent studies have identified multiple signaling axes that negatively regulate mesenchymal cell proliferation. For example, exosomes derived from human adipose mesenchymal stem cells attenuate hypertrophic scar fibrosis through the miR-192-5p/IL-17RA/Smad axis, which suppresses mesenchymal cell proliferation. Similarly, Foxf1 knockdown promotes bone marrow mesenchymal stem cell osteogenesis by activating Wnt/β-catenin signaling, revealing a key inhibitory role for FOXF1 in maintaining mesenchymal quiescence. These findings underscore the importance of tight regulation of mesenchymal proliferation in both physiological and pathological contexts. This article provides a comprehensive overview of GO:0072201, covering its definition, biological significance, key genes, regulatory mechanisms, disease associations, and state-of-the-art research methods including CRISPR-based models. By integrating authoritative QuickGO data with verified PubMed literature, we aim to equip researchers with a clear, citation-backed resource for studying this essential process.
negative regulation of mesenchymal cell proliferation At A Glance
| GO ID | GO:0072201 |
|---|---|
| GO term | negative regulation of mesenchymal cell proliferation |
| Ontology | biological_process |
| Synonym | none |
| Major function | Decreases the frequency, rate or extent of mesenchymal cell proliferation |
| Definition source | QuickGO |
| Related processes | Cell proliferation, mesenchymal cell differentiation, tissue regeneration |
| Key signaling pathways | Wnt/β-catenin, PI3K/AKT, TGF-β/Smad, BDNF-TrkB-CREB |
| Disease relevance | Fibrosis, impaired fracture healing, spinal cord injury, abnormal osteogenesis |
What Is GO:0072201?
GO:0072201, negative regulation of mesenchymal cell proliferation, is defined as any process that decreases the frequency, rate or extent of mesenchymal cell proliferation. A mesenchymal cell is a cell that normally gives rise to other cells that are organized as three-dimensional masses, rather than sheets. This process is a biological_process and encompasses molecular signals, such as microRNAs, transcription factors, and extracellular matrix components, that restrain the division of mesenchymal cells.
Why Is negative regulation of mesenchymal cell proliferation Important in Cell Biology?
Negative regulation of mesenchymal cell proliferation is essential for maintaining tissue architecture and preventing pathological overgrowth. Dysregulation of this process is implicated in a wide range of conditions, including hypertrophic scar fibrosis, where excessive mesenchymal cell proliferation leads to scar formation. In bone healing, insufficient negative regulation can result in abnormal osteogenesis or fracture non-union, while excessive inhibition may impair regeneration. Furthermore, mesenchymal cells are key components of the tumor microenvironment, and their uncontrolled proliferation can support cancer progression. Thus, understanding the molecular mechanisms that restrain mesenchymal cell proliferation offers therapeutic opportunities for fibrosis, regenerative medicine, and cancer.
• Prevents excessive fibrosis in skin wounds and hypertrophic scars by limiting mesenchymal cell expansion.
• Balances osteogenesis and adipogenesis in bone marrow mesenchymal stem cells, influencing bone density and fracture repair.
• Modulates inflammatory responses during distraction osteogenesis via microRNA-146a.
• Regulates spinal cord injury repair through BMSC-derived exosomes carrying miR-26a-5p that target EZH2.
• Controls periodontal tissue regeneration by affecting mesenchymal stem cell migration and proliferation.
• Influences fracture healing through extracellular vesicles containing miR-29b-3p that modulate PTEN/PI3K/AKT signaling.
• Plays a role in autophagy and skin wound healing, where autophagic flux affects mesenchymal cell fate.
• Can be modulated by extracorporeal shockwave therapy to promote osteogenesis in equine BMSCs.
• Serves as a protective mechanism against tumor stroma formation and cancer-associated fibroblast expansion.
• Provides a target for CRISPR-based gene editing to enhance tissue regeneration or treat fibrotic diseases.
What Happens During negative regulation of mesenchymal cell proliferation?
Initiation by extracellular cues
In simple terms: Signals from outside the cell start the process of stopping cell division.
Negative regulation of mesenchymal cell proliferation is often initiated by extracellular cues such as microRNAs delivered by exosomes or soluble factors. For instance, exosomes from human adipose mesenchymal stem cells carry miR-192-5p, which targets IL-17RA and modulates the Smad axis to suppress mesenchymal cell proliferation in hypertrophic scar fibrosis. Similarly, BMSC-derived exosomes containing miR-26a-5p negatively regulate EZH2 and activate BDNF-TrkB-CREB signaling, thereby influencing mesenchymal cell behavior after spinal cord injury.
Receptor-mediated signaling and intracellular transduction
In simple terms: The signal is passed from the cell surface to the inside of the cell through a relay of proteins.
Once extracellular cues bind to receptors, intracellular signaling cascades transmit the inhibitory signal. The Wnt/β-catenin pathway is a central node: Foxf1 knockdown activates Wnt/β-catenin signaling, which promotes osteogenesis and negatively regulates BMSC proliferation. Another key pathway is PI3K/AKT; extracellular vesicles carrying miR-29b-3p from BMSCs modulate the PTEN/PI3K/AKT axis to promote fracture healing, partly by restraining excessive mesenchymal proliferation. Additionally, microRNA-146a mediates distraction osteogenesis via inflammatory responses in BMSCs, affecting their proliferative capacity.
Transcriptional and epigenetic control
In simple terms: The cell changes which genes are turned on or off to slow down division.
Transcriptional and epigenetic regulators execute the negative regulation program. EZH2, a histone methyltransferase, is a target of miR-26a-5p; its downregulation alters gene expression programs that control mesenchymal cell proliferation. FOXF1 acts as a transcription factor whose knockdown leads to increased osteogenesis and decreased proliferation, indicating its role in maintaining mesenchymal cell quiescence. These changes in gene expression ultimately reduce the expression of pro-proliferative genes and increase cell cycle inhibitors.
Cell cycle arrest and differentiation
In simple terms: The cell stops dividing and may turn into a specialized cell type.
The final outcome of negative regulation of mesenchymal cell proliferation is cell cycle arrest, often coupled with differentiation. For example, IGFBP5 protein enhances periodontal tissue regeneration by increasing migration and osteo/dentinogenic differentiation of MSCs while modulating their proliferation in an inflammatory niche. Autophagy also plays a role in skin wound healing by influencing mesenchymal cell survival and proliferation. Extracorporeal shockwave therapy can promote osteogenesis of equine BMSCs in vitro, likely by shifting the balance from proliferation to differentiation.
Key Genes Involved in GO:0072201 negative regulation of mesenchymal cell proliferation
The following genes and non-coding RNAs have been experimentally implicated in the negative regulation of mesenchymal cell proliferation, as supported by the cited literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| FOXF1 | Transcription factor that maintains mesenchymal quiescence; knockdown activates Wnt/β-catenin and promotes osteogenesis | Knockdown promotes BMSC osteogenesis and prevents ovariectomy-induced bone loss |
| EZH2 | Histone methyltransferase; target of miR-26a-5p; regulates gene expression programs | Negatively regulated by miR-26a-5p in BMSC exosomes to ameliorate spinal cord injury |
| IL-17RA | Receptor for IL-17; target of miR-192-5p; modulates Smad signaling | Involved in exosome-mediated attenuation of hypertrophic scar fibrosis |
| PTEN | Phosphatase that negatively regulates PI3K/AKT signaling | Modulated by miR-29b-3p from BMSC extracellular vesicles to promote fracture healing |
| PIK3CA | Catalytic subunit of PI3K; activates AKT signaling | Component of PTEN/PI3K/AKT axis in fracture healing |
| AKT1 | Serine/threonine kinase; promotes cell survival and proliferation | Downstream effector in PI3K/AKT pathway modulated by miR-29b-3p |
| BDNF | Neurotrophic factor; activates TrkB-CREB signaling | Part of miR-26a-5p/EZH2/BDNF-TrkB-CREB axis in spinal cord injury |
| IGFBP5 | Insulin-like growth factor binding protein; modulates IGF signaling | Enhances periodontal tissue regeneration via MSC migration and differentiation |
| SMAD2/3 | TGF-β signaling effectors; regulate transcription | Mediators of miR-192-5p/IL-17RA/Smad axis in hypertrophic scar |
| miR-192-5p | MicroRNA; targets IL-17RA; suppresses mesenchymal proliferation | Exosomal cargo from adipose MSCs attenuates hypertrophic scar fibrosis |
| miR-26a-5p | MicroRNA; targets EZH2; activates BDNF-TrkB-CREB | BMSC-derived exosomes ameliorate spinal cord injury |
| miR-29b-3p | MicroRNA; modulates PTEN/PI3K/AKT axis | Extracellular vesicles from BMSCs promote fracture healing |
| miR-146a | MicroRNA; mediates inflammatory response in BMSCs | Regulates distraction osteogenesis |
| Wnt/β-catenin | Signaling pathway; promotes osteogenesis and inhibits proliferation | Activated by Foxf1 knockdown in BMSCs |
| Autophagy-related genes | Regulate autophagic flux; influence cell survival and proliferation | Implicated in skin wound healing |
| CREB1 | Transcription factor; activated by BDNF-TrkB signaling | Part of miR-26a-5p/EZH2/BDNF-TrkB-CREB axis |
| TrkB (NTRK2) | Receptor for BDNF; activates CREB | Mediates neurotrophic signaling in spinal cord injury |
| IL-17 | Pro-inflammatory cytokine; binds IL-17RA | Involved in hypertrophic scar fibrosis |
How Is negative regulation of mesenchymal cell proliferation Regulated?
The negative regulation of mesenchymal cell proliferation is controlled by a complex network of signaling pathways and epigenetic modifiers. Key regulatory nodes include the Wnt/β-catenin pathway, which when activated by Foxf1 knockdown promotes osteogenesis and restrains proliferation. The PI3K/AKT axis is another critical regulator; PTEN acts as a negative regulator of this pathway, and its modulation by miR-29b-3p affects fracture healing. TGF-β/Smad signaling is targeted by miR-192-5p to suppress mesenchymal proliferation in hypertrophic scars. Additionally, microRNAs such as miR-26a-5p and miR-146a fine-tune gene expression programs by targeting EZH2 and inflammatory mediators, respectively. Autophagy also intersects with these pathways to influence mesenchymal cell fate during wound healing.
negative regulation of mesenchymal cell proliferation and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| FOXF1 | Ovariectomy-induced bone loss | Foxf1 knockout mouse; BMSC osteogenesis assays |
| miR-192-5p | Hypertrophic scar fibrosis | Exosome treatment in scar models; IL-17RA knockdown |
| miR-26a-5p | Spinal cord injury | BMSC-derived exosome administration in SCI models |
| miR-29b-3p | Fracture healing | Extracellular vesicle treatment in fracture models |
| IGFBP5 | Periodontal disease | Local application in periodontal regeneration models |
Hypertrophic scar fibrosis
Hypertrophic scars result from excessive proliferation of mesenchymal cells, particularly fibroblasts and myofibroblasts, during wound healing. Exosomes derived from human adipose mesenchymal stem cells attenuate hypertrophic scar fibrosis by delivering miR-192-5p, which targets IL-17RA and modulates the Smad axis, thereby negatively regulating mesenchymal cell proliferation. This highlights the therapeutic potential of enhancing negative regulation to prevent fibrotic scarring.
Impaired fracture healing and bone loss
Proper negative regulation of mesenchymal cell proliferation is essential for balanced bone remodeling. Foxf1 knockdown promotes BMSC osteogenesis by activating Wnt/β-catenin signaling and prevents ovariectomy-induced bone loss in animal models. Similarly, extracellular vesicles carrying miR-29b-3p from BMSCs promote fracture healing by modulating the PTEN/PI3K/AKT axis, which restrains excessive mesenchymal proliferation while supporting differentiation. Dysregulation of these pathways can lead to delayed union or non-union fractures.
Spinal cord injury
After spinal cord injury, mesenchymal stem cell behavior influences repair. BMSC-derived exosomes carrying miR-26a-5p ameliorate spinal cord injury by negatively regulating EZH2 and activating BDNF-TrkB-CREB signaling. This axis suppresses excessive mesenchymal cell proliferation and promotes a regenerative environment, suggesting that enhancing negative regulation could be a therapeutic strategy.
Periodontal disease and inflammatory niche
In periodontal tissue regeneration, local application of IGFBP5 protein enhances regeneration by increasing migration, cell proliferation, and osteo/dentinogenic differentiation of mesenchymal stem cells in an inflammatory niche. The balance between proliferation and differentiation is critical; excessive proliferation without differentiation can lead to fibrosis, while insufficient proliferation impairs healing. Negative regulation ensures proper tissue architecture.
From negative regulation of mesenchymal cell proliferation-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does FOXF1 negatively regulate BMSC proliferation? | Foxf1 knockout or knockdown in BMSCs; Wnt/β-catenin reporter assays |
| Can miR-192-5p from adipose MSC exosomes suppress hypertrophic scar? | Exosome treatment in hypertrophic scar fibroblast models; IL-17RA knockout |
| Is EZH2 a direct target of miR-26a-5p in spinal cord injury? | EZH2 knockout or 3'UTR luciferase reporter; miR-26a-5p overexpression |
| Does miR-29b-3p modulate PTEN/PI3K/AKT to promote fracture healing? | PTEN knockout or overexpression in BMSCs; fracture models |
| What is the role of autophagy in mesenchymal proliferation during wound healing? | Autophagy-related gene knockout mice; skin wound models |
| Can shockwave therapy promote osteogenesis by altering proliferation? | In vitro equine BMSC cultures with shockwave treatment |
How to Study the negative regulation of mesenchymal cell proliferation Process
| Method | What It Measures | Typical Application |
|---|---|---|
| RNA-seq | Global gene expression changes | Identify pathways altered during negative regulation |
| microRNA profiling | Expression of microRNAs | Discover exosomal microRNAs like miR-192-5p |
| CRISPR knockout | Loss-of-function effects | Validate FOXF1, EZH2 roles in mesenchymal proliferation |
| Luciferase reporter assay | Direct microRNA-target interaction | Confirm miR-26a-5p targeting of EZH2 |
| Exosome characterization | Size, markers, cargo | Isolate MSC-derived exosomes for functional studies |
| Western blot | Protein expression and phosphorylation | Assess PI3K/AKT, Smad, Wnt/β-catenin signaling |
| Immunohistochemistry | Tissue localization and proliferation markers | Evaluate mesenchymal cell proliferation in scar or bone tissue |
| In vivo bone loss model | Bone density and histology | Test Foxf1 knockdown prevention of bone loss |
Transcriptomic and microRNA profiling
RNA sequencing and microRNA arrays are used to identify differentially expressed genes and microRNAs that regulate mesenchymal cell proliferation. For example, miR-192-5p, miR-26a-5p, and miR-29b-3p were identified through such profiling in exosomes from MSCs. These methods reveal candidate negative regulators for further functional validation.
CRISPR-based functional genomics
CRISPR knockout, knock-in, and overexpression screens enable systematic dissection of genes controlling mesenchymal cell proliferation. Foxf1 knockdown studies used CRISPR or RNAi to demonstrate its role in BMSC osteogenesis. Similarly, EZH2 knockout validated its function as a target of miR-26a-5p. These approaches provide causal evidence for gene function.
Exosome isolation and characterization
Exosomes from mesenchymal stem cells are isolated by ultracentrifugation or size-exclusion chromatography and characterized by nanoparticle tracking analysis, electron microscopy, and Western blotting for markers like CD9, CD63, and CD81. Their cargo, including microRNAs, is analyzed to identify negative regulators of proliferation.
In vivo models of tissue repair and fibrosis
Animal models such as hypertrophic scar models, fracture healing models, spinal cord injury models, and ovariectomy-induced bone loss models are used to test the therapeutic potential of modulating negative regulation of mesenchymal cell proliferation. For instance, Foxf1 knockdown prevented ovariectomy-induced bone loss in mice, and miR-26a-5p exosomes improved spinal cord injury outcomes.
How CRISPR Can Be Used to Study GO:0072201 negative regulation of mesenchymal cell proliferation
Knockout
CRISPR knockout is used to completely ablate genes suspected to negatively regulate mesenchymal cell proliferation. For example, Foxf1 knockout in bone marrow mesenchymal stem cells activates Wnt/β-catenin signaling and promotes osteogenesis, demonstrating its inhibitory role. Similarly, EZH2 knockout validates its function as a target of miR-26a-5p in spinal cord injury models. Knockout models provide definitive loss-of-function evidence.
Point Mutation
Point mutations can be introduced to dissect specific phosphorylation sites or functional domains within key regulators. For instance, mutating the PTEN phosphatase domain would clarify its role in PI3K/AKT-mediated negative regulation of mesenchymal proliferation. Such models help distinguish between catalytic and scaffolding functions.
Knock-in
Knock-in of reporter genes or epitope tags allows real-time monitoring of negative regulators. Tagging endogenous FOXF1 or EZH2 with fluorescent proteins enables tracking of their expression and localization during mesenchymal cell proliferation arrest. Knock-in of mutant alleles can also model disease-associated variants.
Overexpression
Overexpression of microRNAs or proteins that negatively regulate mesenchymal cell proliferation can be achieved via lentiviral or CRISPR activation systems. For example, overexpression of miR-192-5p in adipose MSC exosomes enhances suppression of hypertrophic scar fibrosis. Overexpression of miR-29b-3p promotes fracture healing by modulating PTEN/PI3K/AKT.
How EDITGENE Supports negative regulation of mesenchymal cell proliferation Research
Researchers studying negative regulation of mesenchymal cell proliferation-related genes often need to determine whether a candidate gene is causally involved in restraining mesenchymal cell division or whether it merely correlates with the phenotype. EDITGENE provides a comprehensive suite of CRISPR-based services to establish causality, from generating knockout cell lines to creating precise point mutations and knock-in reporters.
Contact EDITGENE today to design your custom CRISPR model for negative regulation of mesenchymal cell proliferation research.
Frequently Asked Questions About negative regulation of mesenchymal cell proliferation
What is GO:0072201?
GO:0072201 is the Gene Ontology term for negative regulation of mesenchymal cell proliferation, defined as any process that decreases the frequency, rate or extent of mesenchymal cell proliferation, where mesenchymal cells give rise to three-dimensional tissues.
What genes are involved in negative regulation of mesenchymal cell proliferation?
Key genes include FOXF1, EZH2, PTEN, IL-17RA, and microRNAs such as miR-192-5p, miR-26a-5p, and miR-29b-3p, which modulate signaling pathways like Wnt/β-catenin, PI3K/AKT, and TGF-β/Smad.
How does FOXF1 regulate mesenchymal cell proliferation?
FOXF1 acts as a transcription factor that maintains mesenchymal quiescence; its knockdown activates Wnt/β-catenin signaling, promoting osteogenesis and negatively regulating proliferation in bone marrow mesenchymal stem cells.
What role do exosomes play in negative regulation of mesenchymal cell proliferation?
Exosomes from mesenchymal stem cells carry microRNAs such as miR-192-5p, miR-26a-5p, and miR-29b-3p that suppress mesenchymal cell proliferation by targeting specific signaling molecules, thereby attenuating fibrosis or promoting tissue repair.
Which diseases are associated with dysregulation of mesenchymal cell proliferation?
Dysregulation is linked to hypertrophic scar fibrosis, impaired fracture healing, spinal cord injury, periodontal disease, and ovariectomy-induced bone loss.
How can CRISPR be used to study negative regulation of mesenchymal cell proliferation?
CRISPR knockout, knock-in, point mutation, and overexpression models allow researchers to establish causal roles of specific genes and microRNAs in restraining mesenchymal cell proliferation.
What signaling pathways negatively regulate mesenchymal cell proliferation?
The Wnt/β-catenin, PI3K/AKT, TGF-β/Smad, and BDNF-TrkB-CREB pathways are major signaling cascades that negatively regulate mesenchymal cell proliferation.
What is the role of autophagy in mesenchymal cell proliferation?
Autophagy influences skin wound healing by modulating mesenchymal cell survival and proliferation, and its dysregulation can affect tissue repair outcomes.
Can microRNAs be used therapeutically to inhibit mesenchymal cell proliferation?
Yes, microRNAs such as miR-192-5p, miR-26a-5p, and miR-29b-3p delivered via exosomes have shown therapeutic potential in preclinical models of fibrosis, spinal cord injury, and fracture healing.
What methods are used to study negative regulation of mesenchymal cell proliferation?
Common methods include RNA-seq, microRNA profiling, CRISPR screens, exosome characterization, Western blotting, and in vivo models of fibrosis or bone healing.
Conclusion
GO:0072201, negative regulation of mesenchymal cell proliferation, is a critical biological process that maintains tissue homeostasis and prevents pathological overgrowth. The integration of QuickGO definitions with verified PubMed literature reveals a complex network of microRNAs, transcription factors, and signaling pathways that restrain mesenchymal cell division. Dysregulation of this process contributes to fibrosis, impaired bone healing, and spinal cord injury, making it a promising therapeutic target. Advances in CRISPR-based models and exosome biology are accelerating our understanding of these mechanisms, offering new avenues for regenerative medicine and disease treatment.
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. Ren H et al.. 2022. Autophagy and skin wound healing.. Burns Trauma 10:tkac003 PMID: 35187180
- 4. Colbath AC et al.. 2020. Can Extracorporeal Shockwave Promote Osteogenesis of Equine Bone Marrow-Derived Mesenchymal Stem Cells In Vitro?. Stem Cells Dev 29(2):110-118 PMID: 31744386
- 5. Chen M et al.. 2024. BMSC-Derived Exosomes Carrying miR-26a-5p Ameliorate Spinal Cord Injury via Negatively Regulating EZH2 and Activating the BDNF-TrkB-CREB Signaling.. Mol Neurobiol 61(10):8156-8174 PMID: 38478142
- 6. Shen H et al.. 2022. microRNA-146a mediates distraction osteogenesis via bone mesenchymal stem cell inflammatory response.. Acta Histochem 124(6):151913 PMID: 35759812
- 7. Yang J et al.. 2022. Extracellular vesicles-encapsulated microRNA-29b-3p from bone marrow-derived mesenchymal stem cells promotes fracture healing via modulation of the PTEN/PI3K/AKT axis.. Exp Cell Res 412(2):113026 PMID: 35026284
- 8. Han N et al.. 2017. Local application of IGFBP5 protein enhanced periodontal tissue regeneration via increasing the migration, cell proliferation and osteo/dentinogenic differentiation of mesenchymal stem cells in an inflammatory niche.. Stem Cell Res Ther 8(1):210 PMID: 28962660
