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PubMed2006

Mesenchymal stem cells and tissue engineering.

Mesenchymal stem cells (MSCs) have become one of the most studied stem cells, especially toward the healing of diseased and damaged tissues and organs. MSCs can be readily isolated from a number of adult tissues by means of minimally invasive approaches. MSCs are capable of self-replication to many passages and, therefore, can potentially be expanded to sufficient numbers for tissue and organ regeneration. MSCs are able to differentiate into multiple cell lineages that resemble osteoblasts, chondrocytes, myoblasts, adipocytes, and fibroblasts and express some of the key markers typical of endothelial cells, neuron-like cells, and cardiomyocytes. MSCs have been used alone for cell delivery or seeded in biomaterial scaffolds toward the healing of tissue and organ defects. After an increasing number of the "proof of concept" studies, the remaining tasks are many, such as to determine MSC interactions with host cells and signaling molecules, to investigate the interplay between MSCs and biological scaffold materials, and to apply MSC-based therapies toward clinically relevant defect models. The ultimate goal of MSC-based therapies has valid biological rationale in that clusters of MSCs differentiate to form virtually all connective tissue during development. MSC-based therapies can only be realized our improved understanding of not only their fundamental properties such as population doubling and differentiation pathways but also translational studies that use MSCs in the de novo formation and/or regeneration of diseased or damaged tissues and organs.

Adipogenesis↗

PubMed2026

The Potential Role of Mesenchymal Stem Cell Therapy for Moderate-to-Severe Atopic Dermatitis: A Systematic Review and Meta-Analysis of Human Clinical Trials.

Despite currently available treatment options for moderate-to-severe atopic dermatitis (AD), some patients fail to achieve adequate disease control. Emerging evidence suggests that mesenchymal stem cells (MSCs) may represent a promising therapeutic option. This systematic review and meta-analysis included four randomized controlled trials (RCTs) and one non-randomized clinical trial. Eligible studies evaluated patients with moderate-to-severe AD treated with MSCs derived from human umbilical cord blood, autologous adipose tissue, and allogeneic bone marrow. PubMed, Embase, and Cochrane were searched from inception to December 2025. Primary outcomes included the proportion of patients achieving ≥50% and ≥75% improvement from baseline in the Eczema Area and Severity Index (EASI) and safety outcomes. The meta-analysis included 236 participants. The pooled EASI-50 response rate at week 12 was 46.76% (95% confidence interval [CI]: 32.36% to 61.72%). EASI-75 response rates were 17.41% (95% CI: 5.56% to 43.03%) at week 12 and 23.97% (95% CI: 16.48% to 33.50%) at week 16. The pooled incidence of treatment-emergent adverse events was 26.86% (95% CI: 19.56% to 35.68%), with infections and infestations 7.97% (95% CI: 4.11% to 14.88%) and gastrointestinal disorders 3.52% (95% CI: 1.33% to 9.01%) being the most frequently reported. MSC-based therapy shows early promise as a potential treatment for moderate-to-severe AD, offering a possible alternative to traditional therapies. However, the current evidence is largely based on small clinical trials, underscoring the necessity for large-scale RCTs to establish the efficacy and safety of MSC-based therapy in broader patient populations.

Humans↗

PubMed2006

[Bone marrow stem cells-based SERCA2a gene therapy for heart failure after acute myocardium infarction].

OBJECTIVE: Explore the possibility of MSC to be used to target delivery of therapeutic gene and evaluate the therapeutic effects among gene therapy, MSC transplantation and MSC-based gene therapy. METHODS: MSC were infected with an adenoviral expression vector carrying SERCA2a. SD female rats were used to make animal model with heart failure after AMI and divided into 4 groups randomly. Group I (n = 7) received SERCA2a gene therapy, group II (n = 7) received MSC transplantation, group III (n = 8) received MSC infected with SERCA2a gene transplantation, and group IV (n = 7) received empty adenoviral vector. Cardiac function was evaluated by echocardiography and physiological recorder. SERCA2a gene and protein expression were evaluated by RT-PCR and Western blot respectively. RESULTS: Compared to group IV, EF and FS of group I, group II and group III were elevated significantly on 14 days after therapy (EF: 67.7 +/- 3.9, 62.6 +/- 4.0, 67.9 +/- 3.7 versus 45.0 +/- 2.2; FS: 33.9 +/- 1.9, 31.1 +/- 2.0, 33.9 +/- 1.9 versus 22.5 +/- 1.1, P < 0.05). While the elevation values of EF and FS began to reduce in group I 14 days after, it continued to increase in both group II and group III. Absolute value of LVEDP at 21 days after treatment was increased in group I, group II and group III compared to group IV (5.3 mm Hg +/- 1.2 mm Hg, 6.0 +/- 1.3 mm Hg, 6.2 mm Hg +/- 1.2 mm Hg versus 1.5 mm Hg +/- 0.2 mm Hg, P < 0.05), as well as absolute value of DP/dtmin (4756 mm Hg/s +/- 270 mm Hg/s, 5028 mm Hg/s +/- 253 mm Hg/s, 5283 mm Hg/s +/- 363 mm Hg/s versus 3201 mm Hg/s +/- 211 mm Hg/s, P < 0.05). DP/dtmax at 21 days after treatment increased in group I, group II and group III compared to group IV (6026 mm Hg/s +/- 281 mm Hg/s, 6278 mm Hg/s +/- 319 mm Hg/s, 7057 mm Hg/s +/- 389 mm Hg/s versus 5293 mm Hg/s +/- 360 mm Hg/s, P < 0.05). SERCA2a expressions and enzyme activity were significantly stronger in group I and group III than in group II and group IV. CONCLUSION: It showed that all MSC transplantation, SERCA2a gene therapy and MSC-based gene therapy could enhance cardiac function. The recovered heart function continued to improve in MSC transplantation group and MSC-based gene therapy group up to 21 days, however slowed down in single gene therapy group in 21 days. Such therapeutic tendency of MSC-based gene therapy was stronger than that of MSC transplantation. Thus, MSC proved an effective platform for the targeted delivery of therapeutic gene.

Animals↗

PubMed2004

Non-hematopoietic human bone marrow contains long-lasting, pluripotential mesenchymal stem cells.

Mesenchymal stem cells (MSC) are considered as potential agents for reconstructive and gene-targeting therapies since they differentiate into various cell-lineages, exhibit an extended survival once injected into a host, and can easily be transfected with engineered DNA. MSC are essentially isolated from hematopoietic bone marrow (BM), a process that is rather invasive and may raise ethical concerns. In an attempt to find an alternative source, we evaluated whether non-hematopoietic (nh)BM recovered from femoral heads of patients undergoing hip arthroplasty contained MSC. Ex vivo, 99% of nhBM cells were CD45(+) leukocytes. After culture, leukocytes were replaced by a homogeneous layer of adherent CD45(-) CD14(-) CD34(-) CD11b(-) CD90(+) HLA-ABC(+) cells. Culture doubling time (mean = 4 days, range 1.6-6.7 days) was not correlated with patient age (27-81 years, n = 16). Amplified cultures supported long-term hematopoiesis, and could be differentiated in vitro into adipocytes and chondrocytes. Moreover, a small fraction of nhBM cells spontaneously expressed MyoD1 and formed myotubes, suggesting that myogenic differentiation also occurred. nhBM contained clonogenic cells whose frequency (1/13,000), doubling time (2.1 days), and maximal amplification (up to 10(6)-fold) were not age-related. All 14 clones analyzed (from five patients, ages 27-78 years) differentiated into at least one mesenchymal lineage, and 66% were bipotential (n = 8/12), or tripotential (n = 2/3). In conclusion, nhBM contains pluripotential mesenchymal progenitors which are similar to hematopoietic BM-derived MSC, and whose biological functions are not altered by aging. Furthermore, if MSC-based therapies hold their promises, nhBM may become the source of choice for responding to the increasing demand for MSC.

Adipocytes↗

PubMed2006

Preclinical evaluation of adult stem cell engraftment and toxicity in the CNS of rhesus macaques.

Congenital neurodegenerative diseases exhibit progressive postnatal neurologic impairment leading to premature death and are intractable to systemic therapies such as bone marrow transplantation. We injected bone marrow-derived mesenchymal stem cells (MSCs) into the CNS of young adult rhesus macaques to evaluate their safety and feasibility as vectors for direct intervention of neurologic disorders. Levels of engrafted male, donor MSCs were quantified in the CNS of female transplant recipients by real-time PCR using an SRY gene-specific probe. Analysis of coronal brain slices encompassing one-third of the total brain volume revealed engraftment levels ranging from 0.026 x 10(-3) to 0.163 x 10(-3)% of the total DNA content of brain tissue. Fine-mapping revealed male DNA distributed within specific anatomic structures along the neuraxis where label-retaining MSCs were visualized in histological sections by immunohistochemistry. Double labeling of sections confirmed that engrafted donor cells lacked expression of the macrophage marker CD68, the astrocytes marker GFAP, and neuronal markers NeuN and MAP2. MSC engraftment had no adverse effects on animal health, behavior, postural and locomotor patterns, or upper limb motor performance evaluated over a 6-month period posttransplantation. Therefore, MSC-based therapies represent a safe alternative for clinical intervention of CNS disorders.

Age Factors↗

PubMed2026

iMSC-derived extracellular vesicles and their miRNA cargo influence inflammation and oxidative damage in an in vitro osteoarthritis model.

Osteoarthritis is a multifactorial chronic joint disease characterized by progressive cartilage degradation and inflammation. Since there is no effective cure, emerging therapeutic approaches, such as mesenchymal stromal cells (MSCs) transplantation, are currently under investigation. However, the clinical translation of MSC-based therapies is hampered by several limitations, such as donor-dependent variability and heterogeneity related to tissue sources. To address these issues, MSCs derived from induced pluripotent stem cells (iMSCs) have been proposed as a more standardized and scalable alternative. Due to the risks of cell-based therapy, extracellular vesicles (EVs), particularly iMSC-EVs (iEVs), could represent a promising cell-free approach for OA treatment. The present study aimed at characterizing iMSC-derived EVs and evaluating their functional role in modulating inflammatory responses and redox balance in an in vitro OA model. Notably, recent evidence highlights the central role of EV-encapsulated microRNAs (EV-miRNAs) in mediating these effects. EVs isolated from iMSC conditioned media were characterized, and their miRNA content was analyzed at different culture passages. Selected miRNAs were subsequently assessed for their biological activity in an in vitro OA model, with a focus on their impact on inflammatory mediators and oxidative stress parameters. Specifically, six miRNAs such as hsa-miR-17-5p, hsa-miR-20a-5p, hsa-miR-21-5p, hsa-miR-29a-3p, hsa-miR-29b-3p, and hsa-miR-29c-3p differentially reflect the anti-inflammatory and antioxidant effects of iMSCs-EVs treatment, suggesting possible synergistic effects. Their combined effect in the in vitro model confirmed their potential modulation in the expression of pro-inflammatory cytokines. Furthermore, their treatment markedly reduced ROS accumulation and oxidative damage, while restoring antioxidant defense systems. These findings support the therapeutic potential of iMSC-derived EVs as a cell-free strategy for OA treatment. The miRNA cargo encapsulated within iEVs appears to play a pivotal role in modulating inflammation and oxidative stress, emphasizing their promise as a novel, minimally invasive approach for disease modification in OA.

MicroRNAs↗

PubMed2005

Murine spinal fusion induced by engineered mesenchymal stem cells that conditionally express bone morphogenetic protein-2.

OBJECT: The authors hypothesized that spinal fusion can be achieved and monitored by using cell-mediated gene therapy. Mesenchymal stem cells (MSCs) genetically engineered to express recombinant human bone morphogenetic protein-2 (rhBMP-2) conditionally, were implanted into the paraspinal muscles of mice to establish spinal fusion. The goal was to demonstrate an MSC-based gene therapy platform in which controlled gene expression is used to obtain spinal fusion in a murine model. METHODS: Mesenchymal stem cells expressing the rhBMP-2 gene were injected into the paravertebral muscle in mice. Bone formation in the paraspinal region was longitudinally followed by performing micro-computerized tomography scanning, histological studies, and an analysis of osteocalcin expression to demonstrate the presence of engrafted engineered MSCs. The minimal period of rhBMP-2 expression by the engineered MSCs required to induce fusion was determined. The results of this study demonstrate that genetically engineered MSCs induce bone formation in areas adjacent to and touching the posterior elements of the spine. This newly formed bone fuses the spine, as demonstrated by radiological and histological studies. The authors demonstrate that injected cells induce active osteogenesis at the site of implantation for up to 4 weeks postinjection. They found that a 7-day induction of rhBMP-2 expression in genetically engineered MSCs was sufficient to form new bone tissue, although the quantity of this bone increased as longer expression periods were implemented. CONCLUSIONS: After their injection genetically engineered MSCs can efficiently form new bone in the paraspinal muscle of the mouse to obtain spinal fusion. The extent and quantity of this newly formed bone can be monitored by controlling the duration of rhBMP-2 gene expression.

Animals↗

PubMed2026

Glycocalyx-edited mesenchymal stem/stromal cell therapy in advanced osteoporosis.

Mesenchymal stem/stromal cells (MSCs) are osteoregenerative; however, their therapeutic efficacy for skeletal conditions is hampered by poor bone-homing ("osteotropism"). In preclinical models, this deficit is correctable by MSC glycocalyx editing to enforce sialylated Lewis X (sLeX) expression, thereby programming osteotropism. We conducted a first-in-human clinical trial (ClinicalTrials.gov: NCT02566655) involving a single intravenous infusion of glycocalyx-edited autologous bone marrow-derived MSCs in ten women with advanced-stage osteoporosis. The protocol-mandated evaluation spanned 2 years and included clinical assessments, radiographic studies, and measurements of bone turnover markers (BTMs), bone tissue area (BTA), and bone mineral density (BMD). Thereafter, fracture and safety monitoring continued for >3 additional years for each patient. No serious adverse events occurred. Fragility fractures were markedly and durably reduced, amidst increased osteoanabolic BTM levels, BTA, and volumetric BMD. These findings indicate that glycocalyx editing effectuates MSC-based osteoporosis therapy and also refute notions that MSCs derived from older persons and/or diseased-tissue sites are biologically compromised.

E-selectin ligand↗

PubMed2000

Gelatin-based resorbable sponge as a carrier matrix for human mesenchymal stem cells in cartilage regeneration therapy.

Adult mesenchymal stem cells (MSCs), found in the bone marrow, have the potential to differentiate into multiple connective tissue types, including cartilage. In this study, we examined the potential of a porous gelatin sponge, Gelfoam, for use as a delivery vehicle for MSCs in cartilage regeneration therapy. Adult human MSCs (hMSCs) were seeded throughout the gelatin sponge after a 2-h incubation period. When cultured for 21 days in vitro in a defined medium supplemented with 10 ng/mL of TGF-beta 3, hMSC/Gelfoam constructs produced a cartilage-like extracellular matrix containing sulfated glycosaminoglycans (s-GAGs) and type-II collagen, as evident upon histologic evaluation. Constructs loaded with a cell suspension of 12 x 10(6) cells/mL produced an extracellular matrix containing 21 microg of s-GAG/microg of DNA after 21 days of culture. This production was more efficient than constructs loaded at higher or lower cell densities, indicating that the initial seeding density influences the ability of cells to produce extracellular matrix. When implanted in an osteochondral defect in the rabbit femoral condyle, Gelfoam cylinders were observed to be very biocompatible, with no evidence of immune response or lymphocytic infiltration at the site. Based on these observations we conclude that Gelfoam resorbable gelatin sponge is a promising candidate as a carrier matrix for MSC-based cartilage regeneration therapies.

Adult↗

PubMed2004

Local ex vivo gene therapy with bone marrow stromal cells expressing human BMP4 promotes endosteal bone formation in mice.

BACKGROUND: Bone loss in osteoporosis is caused by an imbalance between resorption and formation on endosteal surfaces of trabecular and cortical bone. We investigated the feasibility of increasing endosteal bone formation in mice by ex vivo gene therapy with bone marrow stromal cells (MSCs) transduced with a MLV-based retroviral vector to express human bone morphogenetic protein 4 (BMP4). METHODS: We assessed two approaches for administering transduced MSCs. beta-Galactosidase (beta-Gal) transduced C57BL/6J mouse MSCs were injected intravenously via tail vein or directly injected into the femoral bone marrow cavity of non-marrow-ablated syngenic recipient mice and bone marrow cavity engraftment was assessed. BMP4- or beta-Gal-transduced cells were injected into the femoral bone marrow cavity and effects on bone were evaluated by X-ray, peripheral quantitative computed tomography (pQCT), and histology. RESULTS: After tail-vein injection less than 20% of recipient mice contained beta-Gal-positive donor cells in femur, humerus or vertebra marrow cavities combined, and in these mice only 0.02-0.29% of injected cells were present in the bone marrow. In contrast, direct intramedullary injection was always successful and an average of 2% of injected cells were present in the injected femur marrow cavity 24 hours after injection. Numbers of donor cells decreased over the next 14 days. Intramedullary injection of BMP4-transduced MSCs induced bone formation. Trabecular bone mineral density (BMD) determined by pQCT increased 20.5% at 14 days and total BMD increased 6.5% at 14 days and 10.4% at 56 days. CONCLUSIONS: The present findings support the feasibility of using ex vivo MSC-based retroviral gene therapy to induce relatively sustained new bone formation, with normal histological appearance, at endosteal bone sites.

Animals↗

PubMed2001

Incipient analysis of mesenchymal stem-cell-derived osteogenesis.

Tissue regeneration strategies invoke cell-based therapies for effective tissue formation. Current assessment of mesenchymal stem cell (MSC) directed bone regeneration during in vivo assays is dependent on histologic determination of bone formation. It was the aim of this study to determine the relationship between bone sialoprotein (BSP) expression and osteocalcin expression with subsequent osteogenesis occurring in MSC-based implants. RT-PCR assessment of human actin, collagen type I, BSP, and osteocalcin indicated that undifferentiated cells did not express BSP or osteocalcin. Three weeks following implantation, human BSP could be identified in RNAs isolated from the retrieved implants. For every implant from which human BSP cDNA was amplified, parallel implants harvested at 6 weeks demonstrated bone formation at the histologic level. This study confirms that, in the context of the severe combined immunodeficiency disease (SCID) mouse model, culture-expanded, cryopreserved human MSCs have osteogenic potential and demonstrates that implanted cell gene expression can reveal the early onset of bone formation.

Animals↗