Stem Cell-Material Complex: Treatment of Osteoarthritis with Low Cell Dose

Stem Cell-Material Complex: Treatment of Osteoarthritis with Low Cell Dose.  The orthopedic research team constructed a composite of umbilical cord mesenchymal stem cells and gelatin microgels, which can promote cartilage repair and regulate synovial inflammation, reaching 10 times the effect of simple cell therapy at a dose, providing a low-cell dose treatment for osteoarthritis New ideas.

Osteoarthritis (OA) is a common chronic and degenerative joint disease with a very high incidence in middle-aged and elderly people. The number of osteoarthritis (OA) patients worldwide is as high as 355 million, but there is currently no treatment to reverse the progression of the disease. Stem cell treatment of osteoarthritis (OA) has achieved certain results in basic research and clinical trials, but there are still some problems, such as swelling and pain caused by large doses of locally injected cells, and the fate of living cells entering the body is unknown. . These problems restrict the clinical application and promotion of stem cell treatment of osteoarthritis (OA).

In recent years, biomaterials have been widely used to deliver cells or drugs. Compared with 2D cell culture, 3D cell culture has a wider range of cell-cell and cell-matrix interactions, so that cells are in the best growth state and are more conducive to performance. Therapeutic effect.

On February 25, 2021, the Orthopedic Research Team of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology published a titled “Implanted 3D gelatin microcryogel enables low-dose cell therapy for osteoarthritis by preserving the” in Chemical Engineering Journal (IF: 10.652) viability and function of umbilical cord MSCs” research paper.

In this study, a complex UCMSC-GM was constructed, consisting of umbilical cord mesenchymal stem cells (UC-MSCs) and gelatin microcryogel (GM). Studies have proved that: GM can provide a 3D culture environment that can improve cell activity, secretion function and the ability to resist abnormal mechanical loads. The UC-MSCs cultured and delivered by GM remain in the body for a longer time and can continue to secrete growth factors, thereby promoting cartilage repair and regulating synovial inflammation, achieving 10 times the effect of simple cell therapy at a dose of 10 times. It is a low cell for osteoarthritis Dosage therapy provides new ideas.

The team’s previous studies have shown that UC-MSCs can reduce cartilage surface cell damage and inhibit macrophage-mediated synovial inflammation, and the efficacy of three administrations is better than single administration [1]. Based on the results of previous research, this study further explores the feasibility of the material-cell complex to reduce the dose of cell therapy.

In this study, we first used microarray chips to efficiently and quickly prepare gelatin microgel materials, gradually optimizing their mechanical strength, pore size, degradation rate and other properties, and further explored the effects of different cell seeding concentrations and in vitro culture time on UC-MSCs in materials. The proliferation efficiency of UCMSC-GM was affected, and the more efficient construction conditions for UCMSC-GM were screened out.

Figure: Construction of gelatin microgel material

Functional studies have found that compared with 2D cultured UC-MSCs, the 3D cell culture environment provided by GM can promote the release of EGF and TGF-α from stem cells, thereby promoting the growth of chondrocytes. This may be due to the up-regulation of TGF-α converting enzyme (an important metalloprotease that regulates the maturation and release of EGFR ligand protein).

Fig. 2D culture and GM culture growth factor expression

Co-cultivation experiments have found that compared with flat-cultured UCMSCs, UCMSC-GM can promote the proliferation of chondrocytes (Ki67), inhibit their apoptosis (TUNEL), promote their anabolism (Col-2, Sox-9) and inhibit Its catabolism (MMP-13, ADAMTS-5) expression, and EGFR inhibitor Gefitinib (Gefitinib) can block this effect, further proving that UCMSC-GM regulates chondrocyte metabolism by regulating the EGFR signaling pathway State function.

In addition, GM can promote the proliferation of carried cells and inhibit their apoptosis. Because the mechanical environment has an important regulatory effect on the function of stem cells, the researchers simulated the pressure environment in the human knee joint cavity under physiological and pathological conditions in vitro, and found that the activity and function of a simple cell suspension were significantly reduced under abnormal pressure conditions, and The stem cell activity and function decline in UCMSC-GM is not obvious. This shows that GM can effectively protect cell activity and the function of secreting growth factors under pressure, providing a basis for improving the survival of stem cells under abnormal joint cavity pressure in patients with OA and providing a basis for treatment.

In order to explore the fate of stem cells implanted in the joints, the researchers used small animal in vivo imaging (Luciferase) tracing technology to find that compared with the UC-MSCs suspension injected into the joint cavity of mice, the implanted UCMSC-GM was in vivo The retention time is longer, which ensures that the efficiency of cell use is improved. The traditional concept believes that transplanted stem cells colonize and grow in tissue defects and differentiate into damaged tissues, which is the main mechanism for their regeneration.

In this study, UC-MSCs transfected with green fluorescent protein (GFP) was used to locate and trace. It was found that the UC-MSCs transplanted into the joint cavity of mice were mainly colonized on the synovium, meniscus and subchondral bone, with a very small amount distributed in the cartilage. Tissues, suggesting that stem cells repair cartilage damage is mainly paracrine, such as secreting cytokines to enhance endogenous cell repair and inhibit inflammation.

Figure: In vivo localization of UC-MSCs and UCMSC-GM transfected with GFP

In order to clarify the advantages of UCMSC-GM in the treatment of OA, this study used the medial meniscus tibial ligament instability (Destablization of medial meniscus, DMM) surgical model to induce the OA phenotype of mice, and then implanted UC-MSCs into the joint cavity. Suspension and UCMSC-GMs. Histological results show that, compared with UC-MSC cell suspension, UCMSC-GM can promote cartilage repair in OA mice, promote cartilage tissue anabolism (Col-2), and inhibit cartilage catabolism (ADAMTS-5, MMP13) expression.

In addition, joint pain is the most important symptom affecting the quality of life of patients with OA, and it is also the most important factor for patients with OA to seek medical treatment. Studies have shown that synovial inflammation is an important cause of OA pain. Therefore, this study compared the therapeutic effects of UC-MSCs and UCMSC-GM on synovitis, including inhibiting the infiltration of inflammatory cells in synovial tissue (CD68) and the expression of inflammatory factors (IL-1β, TNFα, CCL-3). It will eventually relieve the pain.

In summary, this study clarified the best conditions for GM application, and discussed the promotion of GM’s cell activity and cytokine secretion function. GM enhanced the colonization time of UC-MSCs in the body, thereby significantly improving the therapeutic efficiency of UC-MSCs in repairing cartilage, inhibiting synovial inflammation and relieving joint pain, and found that the transplanted UC-MSCs mainly colonized the synovium, suggesting stem cells A new mechanism for the treatment of OA.

Based on the comprehensive effects of GM on UC-MSCs, it is possible to treat OA with low cell doses, and provide a theoretical basis for the clinical application of biomaterial-assisted stem cell therapy in the treatment of OA. Based on the basis of this research, the team has begun a phase II clinical trial of stem cell treatment of knee OA. (China Clinical Trial Registration Center, registration number: ChiCTR2000039017)

It is reported that the research team (PI: Tian Hongtao) has been engaged in a series of studies on the step treatment of knee osteoarthritis, including the key technology of stem cell treatment of OA (a stem cell clinical research project of the National Health Commission, and a 3551 talent project of Wuhan City) ; Knee-protecting treatment strategies and key technologies for knee arthritis; clinical research on the efficacy of joint replacement day surgery and health economics.

Stem Cell-Material Complex: Treatment of Osteoarthritis with Low Cell Dose

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