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Stromal cell

Stromal cells constitute a diverse and heterogeneous class of cells that form the foundational of organs and tissues throughout the body, providing essential to parenchymal cells while facilitating key physiological processes such as , , and regeneration. These cells, often encompassing subtypes like fibroblasts, , telocytes, and mesenchymal stromal cells (MSCs), originate from mesenchymal precursors and are distributed across various tissues, including , , , and lymphoid organs. Characterized by their multipotent potential and dynamic interactions within the , stromal cells play critical regulatory roles in modulating immune responses, supporting hematopoiesis, and promoting repair through the secretion of bioactive factors with , anti-apoptotic, and immunomodulatory properties. In the niche, for instance, MSCs maintain quiescence and differentiation by expressing markers such as CD73, , and CD105, while negatively lacking hematopoietic indicators like and CD45. Their heterogeneity is evident in -specific adaptations, such as CD34-positive telocytes in the and that aid in myogenic support and , or fibroblastic reticular cells in lymphoid tissues that organize immune cell trafficking. Beyond , stromal cells significantly influence pathological conditions, including cancer progression where cancer-associated fibroblasts remodel the to enhance , and fibrotic diseases driven by dysregulated production. In , their therapeutic potential is harnessed for applications like treating non-union fractures, , and , with clinical trials demonstrating improved outcomes through hMSC infusions that promote repair and reduce . This multifaceted nature underscores stromal cells' evolution from passive supporters to active orchestrators of function and disease dynamics.

Definition and Characteristics

Definition

Stromal cells, originally described in the 19th century as the cellular components of derived from , form the supportive framework of various organs and tissues. Early histological studies, such as those by Maximow in the early building on 19th-century observations, recognized their role in providing a microenvironment for cellular processes like hematopoiesis, though the term "stromal" gained prominence later with the identification of specific progenitor populations in . In modern biological usage, a key subset of stromal cells, mesenchymal stromal cells (MSCs), is defined by the minimal criteria established by the International Society for Cell & Gene Therapy (ISCT) in 2006. These criteria emphasize their identity as non-hematopoietic, multipotent cells that provide structural and functional support to parenchymal cells—the primary functional cells of organs—through secretion of components like and , as well as through . In culture, they exhibit plastic adherence and a fibroblast-like , enabling expansion while maintaining self-renewal capacity. The ISCT's 2019 position statement further clarifies the , recommending "mesenchymal stromal cells" over "mesenchymal stem cells" unless rigorous and evidence demonstrates true stemness, as current definitions lack definitive proof of extensive hematopoietic or tissue reconstitution potential. This distinction underscores their role as supportive progenitors rather than universal stem cells, prioritizing functional assays for therapeutic applications.

Phenotypic Markers and Differentiation Potential

Stromal cells, particularly mesenchymal stromal cells (MSCs), are identified phenotypically through standardized surface marker expression profiles established by the International Society for Cell & Gene Therapy (ISCT). The minimal criteria require that at least 95% of the cell population express CD73, , and CD105, while fewer than 2% express hematopoietic or endothelial markers such as CD11b, , , , CD45, or , as verified by analysis. These criteria, proposed in and reaffirmed in subsequent ISCT position statements, ensure the distinction of MSCs from other cell types by confirming their fibroblast-like properties and lack of lineage commitment. A hallmark of stromal cell identity is their trilineage potential, assessed through assays that induce and confirm adipogenic, osteogenic, and chondrogenic lineages. For , cells are cultured in media supplemented with dexamethasone, insulin, indomethacin, and 3-isobutyl-1-methylxanthine for 2-3 weeks, followed by fixation and with to visualize intracellular lipid droplets as red inclusions under light microscopy. Osteogenic involves to β-glycerophosphate, ascorbic acid, and dexamethasone for 3-4 weeks, with calcium deposits detected by , appearing as orange-red nodules. Chondrogenesis is induced in pellet cultures with TGF-β, dexamethasone, and ascorbic acid over 3 weeks, confirmed by Alcian Blue of glycosaminoglycans in the , yielding blue coloration. These s, integral to ISCT criteria, demonstrate the multipotency of stromal cells, though the efficiency and potency can vary depending on the tissue source. Functional assays further validate stromal cell clonogenicity, with the colony-forming unit-fibroblast (CFU-F) serving as a key measure of proliferative potential. In this , single-cell suspensions are plated at low density (e.g., 10-100 cells/cm²) in standard culture media, incubated for 10-14 days, and stained with to enumerate fibroblast-like colonies comprising at least 50 cells, indicating self-renewal capacity. The trilineage remains the defining feature, but CFU-F frequency typically ranges from 1 in 10,000 to 1 in 100,000 nucleated cells in primary isolates, reflecting their rarity and underscoring the need for expansion in culture. Recent research from 2024-2025 has identified additional markers to refine stromal cell subtypes, such as Sca-1 (stem cell antigen-1) in murine models, where high Sca-1 expression on MSCs correlates with enhanced metastatic support in contexts and improved purification of adipose-derived cells with superior proliferative and potential. These findings build on core ISCT markers by highlighting context-specific variations, particularly in preclinical studies.

Sources and Types

Primary Tissue Sources

Stromal cells, particularly mesenchymal stromal cells (MSCs), are primarily sourced from , which serves as the gold standard due to its established role in supporting hematopoiesis. In bone marrow aspirates, MSCs constitute approximately 0.001-0.01% of nucleated cells, yielding about 100-1,000 cells per milliliter of marrow. Other key tissue sources include , which provides a higher yield of MSCs compared to , with approximately 5,000 cells per gram of or 0.35-1 million cells per gram, representing 1-10% of the stromal vascular fraction. and placental tissues are notable for their MSCs' high proliferative capacity and low , making them advantageous for allogeneic applications. Additional sources encompass dental pulp, , and , each offering accessible MSCs with tissue-specific properties. Isolation of MSCs from these sources typically involves density gradient centrifugation, such as using to separate mononuclear cells, followed by selective plastic adherence in , where MSCs attach to while hematopoietic cells are removed. Yield comparisons highlight adipose tissue's superiority over on a per-gram basis, facilitating larger-scale harvests for clinical use. Quality of sourced MSCs is influenced by donor age, with older individuals exhibiting reduced proliferative potential and increased markers, such as beta-galactosidase activity and shortened telomeres, leading to diminished therapeutic efficacy. In contrast, placental-derived MSCs demonstrate enhanced "youthful" potency, effectively modulating aging-related neural pathways and preserving immunomodulatory functions in recent studies. Differentiation potential can vary slightly by source, with adipose-derived MSCs often showing robust adipogenic capacity.

Subtypes and Variants

Mesenchymal stromal cells (MSCs) represent the primary variant of stromal cells, characterized by their perivascular origin and close association with blood vessels, where they often manifest as or pericyte precursors. These cells exhibit multipotency, differentiating into lineages such as osteoblasts, adipocytes, and chondrocytes, and are identified by their location in the vascular niche across various tissues. , as a key subset of MSCs, wrap around capillaries and contribute to vessel stability and homeostasis. Specialized subtypes of stromal cells include cancer-associated fibroblasts (CAFs), defined as activated fibroblasts within the tumor stroma that express markers like α-smooth muscle actin and fibroblast activation protein. Another distinct subtype is Sca-1high MSCs in murine models, a population highly expressing the antigen-1 (Sca-1) marker, identified in 2025 research as enriched in lung-derived MSCs with unique functional properties. cells, a pluripotent-like subpopulation of MSCs expressing SSEA-3 and capable of differentiating into cells of all three germ layers, show increased ratios under stress conditions, as demonstrated in 2025 studies on marrow-derived cells. Environmental factors induce variants in stromal cells, such as hypoxia-adapted MSCs that upregulate pluripotency genes including Oct4 through hypoxia-inducible factor-2α (HIF-2α) activation, enhancing stemness under low-oxygen conditions. Inflammatory-primed MSCs, exposed to cytokines like IFN-γ or TNF-α, exhibit a shifted secretome with altered production of immunomodulatory factors, promoting enhanced modulation compared to unprimed cells. Beyond core markers like CD73, , and CD105, molecular distinctions define stromal cell variants; for instance, CD146 expression identifies pericyte-like subsets with vascular regulatory functions, while NG2 marks contractile involved in vessel tone control. Placental sources yield variants with heightened immunomodulatory potential, though detailed origins are covered elsewhere.

Physiological Functions

Support in Hematopoiesis

Stromal cells in the microenvironment form critical architectural components of the hematopoietic niches, including the endosteal niche adjacent to the surface and the perivascular niche surrounding sinusoidal vessels. These cells, particularly mesenchymal stromal cells (MSCs) and CXCL12-abundant reticular (CAR) cells, provide a supportive scaffold that maintains (HSC) quiescence and facilitates their homing and retention through the expression of (also known as SDF-1). The CXCL12-CXCR4 signaling axis is essential for anchoring HSCs within these niches, preventing their premature or into the bloodstream. Through paracrine signaling, stromal cells secrete key cytokines such as stem cell factor (SCF, also known as KIT ligand) and thrombopoietin (TPO), which promote HSC survival, self-renewal, and lineage commitment. SCF supports the proliferation and maintenance of HSCs and multipotent progenitors, while TPO regulates megakaryopoiesis and contributes to overall HSC pool stability. Additionally, stromal cells mediate direct cell-cell interactions via adhesion molecules like vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), which bind to integrins on HSCs (e.g., VLA-4), enhancing their attachment and polarization within the niche to sustain quiescence and enable controlled differentiation. These mechanisms collectively form a physical and biochemical scaffold that balances HSC dormancy with the demands of blood cell production. Experimental evidence from co-culture assays demonstrates that stromal cells significantly enhance the of myeloid and natural killer (NK) cells from hematopoietic progenitors. For instance, MSCs in co-culture with CD34+ cells promote myeloid differentiation through secretion and cell contact, leading to increased production of granulocytes and monocytes. Similarly, stromal support has been shown to drive NK cell maturation from early progenitors, with enhanced observed . Recent advancements, such as 2025 models of artificial organoids (AMOs), have recapitulated these interactions in a three-dimensional system, where MSCs efficiently support myeloid and NK lineage commitment from induced pluripotent cell-derived progenitors, mimicking native functionality. Stromal cells form the non-hematopoietic compartment that regulates dynamics. They modulate self-renewal via signaling, where stromal-expressed ligands like Jagged-1 and Delta-like 1 activate receptors on , promoting their expansion and repopulation capacity without inducing exhaustion. This regulatory role ensures long-term hematopoiesis, with disruptions in stromal components leading to impaired maintenance in preclinical models.

Role in Tissue Maintenance and Homeostasis

Stromal cells play a pivotal role in maintaining and by synthesizing essential components of the (), including and types I and IV, which form basement membranes in various organs. In the , mesenchymal stromal cells produce these elements to support alveolar septation, epithelial maturation, and overall structural integrity during and repair processes. Similarly, in the liver, hepatic stellate cells—a key stromal population—secrete types I and IV along with to reinforce basement membranes in the space of Disse, ensuring proper organization and sinusoidal patency under steady-state conditions. These contributions prevent mechanical instability and facilitate nutrient exchange, underscoring stromal cells' foundational support for organ . Beyond structural provision, stromal cells sustain parenchymal cell populations through targeted signaling interactions. In the gut, subepithelial stromal fibroblasts interact with + epithelial s via Wnt ligands such as Wnt2b and amplifiers like RSPO3, driving crypt-villus axis renewal every 3–5 days to preserve mucosal and epithelial turnover. Recent 2025 studies on colonic emphasize how these cells orchestrate Wnt/β-catenin pathway activation to maintain intestinal niches and prevent dysregulated proliferation during . This stromal-epithelial exemplifies how non-hematopoietic support mechanisms ensure long-term renewal across organs. Stromal cells also promote vascular through angiogenic factors and functions. , a specialized stromal subtype, secrete (VEGF-A) in response to local cues, enhancing endothelial cell survival, migration, and stabilization to maintain blood flow and prevent leakage. By wrapping around vessels and modulating PI3K/AKT signaling, ensure microvascular integrity, which is crucial for nutrient delivery and waste removal in tissues like the and gut. In response to mild tissue , stromal cells engage feedback loops involving transforming growth factor-β (TGF-β) to coordinate repair while preserving . TGF-β signaling in fibroblasts and induces controlled remodeling, epithelial re-establishment, and without excessive deposition, relying on SMAD-mediated regulation of and to restore balance. This dynamic response highlights stromal cells' capacity to integrate signals for adaptive across multiple tissues.

Immunomodulatory Effects

Anti-inflammatory Mechanisms

Stromal cells, particularly mesenchymal stromal cells (MSCs), exert anti-inflammatory effects by suppressing effector immune cells through multiple pathways. These cells inhibit T-cell primarily via the production of (IDO), which depletes essential for T-cell activation, and (PGE2), which interferes with T-cell signaling and production. Similarly, MSCs suppress B-cell production and terminal by inducing arrest and through soluble factors like TGF-β and direct cell-cell interactions involving / pathways. For natural killer () cells, MSCs modulate , , and secretion, such as IFN-γ, by secreting IDO and PGE2, thereby reducing NK cell effector functions without inducing . In addition to effector suppression, stromal cells release soluble mediators that dampen immune responses. Key among these are transforming growth factor-β (TGF-β) and interleukin-10 (IL-10), which promote regulatory T-cell differentiation and inhibit pro-inflammatory production by macrophages and T cells. Stromal cell-derived extracellular vesicles (EVs) also contribute to effects by transferring bioactive molecules that modulate immune cell polarization and profiles, as demonstrated in recent studies on neurodegenerative and inflammatory diseases. Upon stimulation with IFN-γ, MSCs upregulate inducible (iNOS), leading to (NO) production that further suppresses T-cell proliferation and shifts macrophage polarization toward an M2 phenotype. Cell-cell interactions also contribute significantly to the repertoire of stromal cells. MSCs express programmed death-ligand 1 () on their surface and secrete soluble , which binds PD-1 on activated T cells, inducing T-cell anergy, exhaustion, and while sparing regulatory T cells. Recent studies have highlighted a mechanism involving modulation, where MSCs induce aggregation in the , facilitating the release of extracellular vesicles that promote resolution of via immune rebalancing pathways and reduced systemic activation. The anti-inflammatory potential of stromal cells is highly context-dependent, often requiring priming with low levels of IFN-γ and TNF-α to optimize their secretome toward immunosuppressive factors like IDO, PGE2, and TGF-β, while higher cytokine concentrations can shift toward pro-inflammatory responses.

Pro-inflammatory Mechanisms

Stromal cells, particularly mesenchymal stromal cells (MSCs), exhibit pro-inflammatory mechanisms when exposed to elevated levels of interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), which serve as licensing signals to shift their phenotype toward immune amplification. This activation triggers intracellular pathways such as JAK/STAT1 for IFN-γ and NF-κB for TNF-α, leading to synergistic upregulation of pro-inflammatory cytokine production, including interleukin-6 (IL-6) and interleukin-8 (IL-8). These cytokines promote the chemotaxis and recruitment of monocytes to sites of inflammation, enhancing the innate immune response. Optimal licensing occurs with a 1:1 ratio of IFN-γ and TNF-α at approximately 60 ng/mL, followed by overnight exposure, which can double the immunomodulatory potency in peripheral blood mononuclear cell suppression assays while favoring pro-inflammatory effector functions. In this pro-inflammatory state, stromal cells further support adaptive immunity by upregulating major histocompatibility complex class II (MHC-II) expression, which enhances their capacity for and interaction with T cells. This MHC-II induction, primarily driven by IFN-γ stimulation, allows stromal cells to modulate (DC) maturation, promoting a more immunogenic that presents antigens effectively to naive T cells. Concurrently, licensed stromal cells influence differentiation, supporting Th1 and Th17 polarization in environments with activated + T cells by sustaining pro-inflammatory milieus like IL-6 and IL-12, thereby amplifying cell-mediated and humoral responses against pathogens. Such effects contrast with their baseline default but highlight their contextual adaptability in immune regulation. Evidence for this emerges from priming studies, where stromal cells undergo a phenotypic switch from immunosuppressive to pro-inflammatory states upon prolonged exposure to high-dose inflammatory cytokines, as demonstrated by increased secretion of and adhesion molecules like and VCAM-1. Recent 2025 research on Sca-1^high stromal variants further illustrates this, showing their enhanced production of such as , , and CCL7, which recruit pro-inflammatory myeloid cells including macrophages and neutrophils to amplify local during metastatic processes. These findings underscore the of stromal cells in responding to environmental cues. This pro-inflammatory activation represents a transient in stromal cell function, facilitating initial clearance and immune cell orchestration before feedback mechanisms, such as downregulation or IL-10 induction, promote and repair. By temporarily boosting effector responses, stromal cells ensure balanced without chronic escalation.

Role in Pathology

In Cancer Progression and Microenvironment

Stromal cells within the tumor microenvironment, often termed tumor-associated stromal cells (TASCs), are recruited to tumor sites primarily through the stromal cell-derived factor-1 (SDF-1, also known as CXCL12)/C-X-C chemokine receptor type 4 (CXCR4) axis, where tumor cells or surrounding stroma secrete SDF-1 to attract CXCR4-expressing mesenchymal stromal cells from bone marrow or adjacent tissues, thereby facilitating their integration into the supportive tumor niche. Once incorporated, TASCs promote tumor angiogenesis and cell survival by secreting vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6), which stimulate endothelial cell proliferation and protect cancer cells from apoptosis under hypoxic or therapeutic stress conditions. A prominent subtype of TASCs, carcinoma-associated fibroblasts (CAFs), particularly those expressing alpha-smooth muscle actin (α-SMA), actively drive epithelial-mesenchymal transition (EMT) in adjacent carcinoma cells via secretion of hepatocyte growth factor (HGF), which activates the c-MET receptor to enhance motility and invasive potential. Additionally, α-SMA+ CAFs contribute to tumor invasion by remodeling the extracellular matrix (ECM) through elevated production of matrix metalloproteinases (MMPs) such as MMP-2 and MMP-9, which degrade basement membranes and create tracks for cancer cell dissemination. In supporting metastasis, recent 2025 research has highlighted the role of Sca-1-high mesenchymal stromal cells (MSCs) in the , which recruit myeloid immune cells such as macrophages and neutrophils via secretion (among other factors) to precondition the pre-metastatic niche and enhance colonization of pulmonary tissues. Complementary 2025 analyses of single-cell sequencing data from tumors have revealed significant stromal heterogeneity, identifying distinct subpopulations that correlate with metastatic propensity through differential profiles, underscoring the need for subtype-specific targeting. While stromal cells predominantly exhibit pro-tumorigenic functions in most solid tumors by fostering growth and immune evasion—such as through TGF-β-mediated suppression of T-cell infiltration—they can adopt anti-tumor roles when genetically engineered, for instance, to deliver interferon-β and inhibit tumor vascularization in preclinical models. This immunomodulatory aspect briefly aids tumor immune evasion by dampening cytotoxic responses, though detailed mechanisms are addressed elsewhere.

In Inflammatory and Fibrotic Diseases

Stromal cells play a central role in the of fibrotic diseases by differentiating into , primarily through the TGF-β/Smad signaling pathway, which drives excessive (ECM) deposition and tissue scarring. In this process, TGF-β1 binds to its receptors on fibroblasts, activating canonical Smad2/3-dependent signaling that promotes myofibroblast and the production of ECM components such as and . This mechanism is particularly evident in organ-specific , where persistent activation leads to pathological remodeling; for instance, in liver cirrhosis, hepatic stellate cells—a type of stromal cell—undergo myofibroblast , resulting in excessive deposition and progression to end-stage . Similarly, in (IPF), alveolar fibroblasts contribute to lung stiffness through aberrant ECM accumulation, exacerbating . Beyond , stromal cells amplify chronic in diseases like (IBD) by secreting pro-inflammatory cytokines such as IL-6, which promotes Th17 cell differentiation and sustains immune-mediated tissue damage. In the intestinal mucosa of IBD patients, fibroblasts upregulate IL-6 in response to Th17-derived signals like IL-17, creating a feedback loop that enhances Th17 responses and drives mucosal toward . Recent studies on placental mesenchymal stromal cells (MSCs) have highlighted potential regulatory pathways, showing that of the AMPK-FXR axis in these cells can mitigate gut in models by reducing pro-inflammatory cytokine release and restoring barrier integrity. In (), synovial stromal cells, particularly fibroblasts, perpetuate joint inflammation and erosion by forming a pannus-like structure that invades and , with upregulated expression of stromal markers correlating to disease severity. These cells respond to inflammatory cues by secreting and cytokines that recruit immune effectors, maintaining chronic . In (systemic sclerosis), dermal stromal cells, including LGR5-expressing fibroblasts, drive skin through dysregulated production and vascular alterations, leading to progressive skin thickening and internal organ involvement. Disease progression in these conditions is further exacerbated by persistent injury signals that induce stromal cell , triggering the (SASP) and amplifying and . Senescent stromal cells, such as fibroblasts in fibrotic lungs or hepatic stellate cells, release SASP factors including IL-6 and TGF-β, which perpetuate activation and deposition in a self-sustaining manner. This senescent state, often linked to unresolved damage, contributes to the transition from acute injury to chronic fibrotic disease across multiple organs.

Therapeutic Applications

Regenerative and Tissue Repair Therapies

Stromal cells, particularly mesenchymal stromal cells (MSCs), play a pivotal role in regenerative therapies by leveraging both direct into tissue-specific lineages and paracrine mechanisms to promote repair. In direct differentiation, MSCs can integrate into damaged tissues and contribute to structural regeneration, such as forming chondrocytes for repair or osteoblasts for . Paracrine effects are mediated through secreted factors, including growth factors like (VEGF) and hepatocyte growth factor (HGF), which stimulate and in surrounding cells. Additionally, MSC-derived exosomes carrying microRNAs (miRNAs), such as miR-126 and miR-21, enhance endothelial and to support vascular repair. Clinical applications of stromal cells in repair have advanced to phase III s, demonstrating efficacy in specific conditions. For , intra-articular injections of adipose-derived MSCs have shown significant improvements in pain scores and joint function, with a phase III randomized, double-blind reporting a mean WOMAC score reduction of 21.7 points at 6 months compared to 14.3 points in (P = .002). In , bone marrow-derived MSCs administered intravenously post-infarct have improved left ventricular (LVEF) by an average of 4-6% in meta-analyses of randomized controlled trials, attributed to reduced infarct size and enhanced cardiac remodeling. Recent advances in 2025 have focused on enhancing stromal cell potency for broader regenerative applications. preconditioning of multilineage-differentiating stress-enduring () cells, a pluripotent subset of MSCs, increases their yield by up to twofold and upregulates pluripotency genes like OCT4 and NANOG, enabling more efficient tissue regeneration in preclinical models of and . models incorporating stromal cells as supportive scaffolds have also progressed, with bone marrow-derived MSCs integrated into 3D structures to mimic hematopoietic niches and promote myeloid differentiation, offering scalable platforms for . Despite these promising developments, challenges persist in stromal cell therapies, including low engraftment rates typically below 5% due to poor in hostile microenvironments and rapid clearance by the host . To address this, scaffolds such as hydrogel-based matrices have been employed to improve cell retention and delivery, enhancing osteogenic potential in defect models by providing mechanical support and localized factor release.

Immunomodulatory and Anti-inflammatory Therapies

Stromal cells, particularly mesenchymal stromal cells (MSCs), have been investigated in clinical trials for their immunomodulatory properties in treating autoimmune diseases, where they help suppress aberrant immune responses and reduce disease flares. In , intravenous administration of autologous MSCs has demonstrated potential to attenuate symptoms by upregulating , an that inhibits T-cell and promotes regulatory T-cell expansion, leading to reduced relapse rates in phase I/II trials involving doses of 1-2 × 10^6 cells/kg. A phase I/II dose-finding study using human umbilical cord-derived MSCs in MS patients further confirmed and preliminary in modulating immune activity without significant adverse events. Similarly, in following , MSCs have shown success in phases II and III trials by dampening donor T-cell reactivity and release, with overall response rates reaching 70% at 28 days post-infusion in steroid-refractory acute GVHD cases. As of 2025, regulatory efforts continue internationally, with the reviewing remestemcel-L for similar indications. For acute inflammatory conditions, MSCs target excessive immune activation, such as storms. Clinical trials from 2020 to 2022 for (ARDS) associated with reported that intravenous MSC infusions reduced inflammatory biomarkers like IL-6 and TNF-α, improving oxygenation and lowering mortality risk in severe cases, as evidenced by a of randomized controlled trials showing significant decreases in levels and secondary outcomes like ventilator-free days. In , placental-derived MSCs have emerged as a ; a 2025 study demonstrated that these cells alleviate intestinal inflammation and repair barrier function by secreting IGFBP-4, which activates the AMPK-FXR pathway to suppress pro-inflammatory signaling, resulting in clinical remission in refractory patients. Delivery of MSCs primarily occurs via intravenous , leveraging their intrinsic homing ability to inflamed sites through interactions with like SDF-1 and molecules such as , which guide cells to areas of tissue damage and immune dysregulation. Standard dosing regimens range from 1 to 2 × 10^6 cells/kg body weight, administered as single or multiple s spaced 7 days apart, ensuring safety and feasibility across trials in autoimmune and inflammatory settings. Meta-analyses of therapies in immunomodulatory applications indicate response rates of 50-70% in conditions like GVHD and ARDS, with complete responses in 25-30% of cases and improved overall survival, particularly when combined with standard treatments. By 2025, the U.S. (FDA) approved Ryoncil, an allogeneic bone marrow-derived product, for steroid-refractory acute GVHD in pediatric patients, marking the first such approval for an immunomodulatory stromal cell therapy and paving the way for broader indications in autoimmune disorders.