It’s what they secrete

Posted on September 11, 2019 Written by nhriordan Leave a Comment

In my recent talks, I’ve often highlighted that the secretions of MSCs are what is behind their therapeutic effect – this is supported by the findings of several publications investigating their paracrine properties. This 2019 paper extensively reviews the recent research about the role of secreted extracellular vesicles of UC-MSC. The authors go over 35 studies that used extracellular vesicles from UC-MSC to treat diverse conditions in animal models and in vitro (in the lab), with very positive outcomes.

2019 Jun 28. doi: 10.1002/jcp.29004.

Human umbilical cord mesenchymal stem cell-derived extracellular vesicles: A novel therapeutic paradigm.

Abbaszadeh H, Ghorbani F, Derakhshani M, Movassaghpour A, Yousefi M.

Abstract

Mesenchymal stem cells (MSCs) have been revealed to hold great potential for the development of new treatment approaches for various diseases. However, the clinical use of these cells is limited due to their tumorigenic effects. The therapeutic benefits of MSCs are largely dependent on paracrine factors including extracellular vesicles (EVs). EVs are nano-sized bilayer membrane structures containing lipids, microRNAs and proteins which play key roles in cell-to-cell communications. Because of their lower immunogenicity, tumorigenicity, and easier management, EVs have emerged as a new promising alternative to whole-cell therapy. Therefore, this paper reviews current preclinical studies on the use of EVs derived from human umbilical cord MSCs (hucMSCs) as a therapeutic approach in treatment of several diseases including neurological, cardiovascular, liver, kidney, and bone diseases as well as the cutaneous wound, inflammatory bowel disease, cancers, infertility, and other disorders.

PMID: 31254289 DOI: 10.1002/jcp.29004

UC-MSCs clear apoptotic cells (lupus)

Posted on September 6, 2019 Written by nhriordan Leave a Comment

Apoptotic cells are cells that have reached the end of their life cycle. They would normally be cleared by other cells the body that recognize an “eat me” signal to suppress them. However, patients with lupus have difficulty clearing those apoptotic cells – while already dead, the cells continue releasing secretions that can offset the balance of the immune system, leading to eventual necrosis (death of tissue). In this 2019 study, researchers found that mesenchymal stem cells derived from umbilical cord (UC-MSCs) were able to “eat” apoptotic cells both in the lab and in 22 patients lupus patients. UC-MSCs were activated in the presence of apoptotic cells and secreted immunosuppressive factors (COX2 expression and PGE2 production to inhibit T cell response). This is the first time this mechanism was reported for lupus.

2019 Jul;45:341-350. doi: 10.1016/j.ebiom.2019.06.016.

Clearance of apoptotic cells by mesenchymal stem cells contributes to immunosuppression via PGE2.

Zhang Z, Huang S, Wu S, Qi J, Li W, Liu S, Cong Y, Chen H, Lu L, Shi S, Wang D, Chen W, Sun L.

Abstract

BACKGROUND:

Defective clearance of apoptotic cells (ACs) has been suggested to be involved in the pathogenesis of systemic lupus erythematosus (SLE). Mesenchymal stem cells (MSCs) exhibit promising therapeutic effects on SLE, but whether MSCs phagocytose ACs and contributes to the underlying mechanism in the treatment of SLE remain unknown.

METHODS:

Human umbilical cord (UC) MSCs were co-cultured with ACs, and the engulfment of ACs by MSCs was either detected by flow cytometry or observed under confocal laser scanning microscope. Peripheral blood mononuclear cells (PBMCs) from healthy controls (HCs) were cultured in MSC conditioned medium (MCM) or MSC exposed to ACs (AC-MSC) conditioned medium (ACMCM), and then CD4⁺ T cell proliferation was detected. Soluble factors including prostaglandin (PG)E2 in the supernatants of MSCs and AC-MSCs, as well as in the mouse peritoneal lavage fluids (PLF) were determined by enzyme-linked immunosorbent assay (ELISA). Cyclooxygenase (COX)2 inhibitors and siRNA transfection were utilized to determine the function of COX2/PGE2 in AC-MSC-mediated immunosuppression. PGE2 metabolites (PGEM) in the plasma of SLE patients were measured before and 24 h after MSC transplantation respectively.

FINDINGS:

Human UC MSCs possessed the ability to engulf ACs. AC-MSCs increased MSC-mediated suppression of CD4⁺ T cell proliferation compared to MSCs alone. Mechanistically, ACs stimulated MSCs to express COX2 and consequently produced PGE2 that inhibited T cell responses. NF-κB signalling pathway mediated the activation of COX2/PGE2 in AC-MSCs. Importantly, in patients with SLE, the plasma PGEM levels increased significantly in those with reduced apoptotic mononuclear cells in peripheral blood after MSC transplantation.

INTERPRETATION:

Clearance of ACs by MSCs contributes to immunosuppressive function via increasing PGE2 production. These findings reveal a previously unrecognized role of MSC-mediated phagocytosis of ACs in MSC-based immunotherapy.

PMID: 31248835 PMCID: PMC6642220 DOI: 10.1016/j.ebiom.2019.06.016

Spinal cord injury patients receiving BMMSC show improvements compared to control group

Posted on April 9, 2019 Written by nhriordan Leave a Comment

This 2013 study features a treatment group (who received bone marrow mesenchymal stem cells) and a control group (who did not receive cells). 20 patients were in the treatment group and 20 in the control group, for a total of 40 patients with spinal cord injuries. The MSCs were harvested from the bone marrow of the participants. Only mild adverse events (fever and headache) were reported in the treatment group. Patients who did not receive cells showed no improvement after 6 months. Half (10/20) of those who received bone marrow MSC showed improvements in motor or sensory function, or in ASIA grades (9/20). The differences in scores between those who did not receive cells and those who did receive BMMSC were statistically significant.

Brain Res. 2013 Oct 2;1533:73-9. doi:10.1016/j.brainres.2013.08.016. Epub 2013 Aug 12.

Transplantation of autologous bone marrow mesenchymal stem cells in the treatment of complete and chronic cervical spinal cord injury.

Dai G, Liu X, Zhang Z, Yang Z, Dai Y, Xu R.

Abstract

Neuronal injuries have been a challenging problem for treatment, especially in the case of complete and chronic cervical spinal cord injury (SCI). Recently, particular attention is paid to the potential of stem cell in treating SCI, but there are only few clinical studies and insufficient data. This study explored the efficacy of autologous bone marrow mesenchymal stem cells (BMMSCs) transplantation in the treatment of SCI. Forty patients with complete and chronic cervical SCI were selected and randomly assigned to one of the two experimental groups, treatment group and control group. The treatment group received BMMSCs transplantation to the area surrounding injury, while the control group was not treated with any cell transplantation. Both the transplant recipients and the control group were followed up to 6 months, postoperatively. Preoperative and postoperative neurological functions were evaluated with AIS grading, ASIA score, residual urine volume and neurophysiological examination. Results showed that in the treatment group 10 patients had a significant clinical improvement in terms of motor, light touch, pin prick sensory and residual urine volume, while nine patients showed changes in AIS grade. Neurophysiological examination was consistent with clinical observations. No sign of tumor was evident until 6 months postoperatively. In the control group, no improvement was observed in any of the neurological functions specified above. BMMSCs transplantation improves neurological function in patients with complete and chronic cervical SCI, providing valuable information on applications of BMMSCs for the treatment of SCI.

PMID: 23948102

Early study (2008) of bone marrow stem cells for spinal cord injury

Posted on April 5, 2019 Written by nhriordan Leave a Comment

Research on the treatment of spinal cord injury with cells from bone marrow aspirate was already ongoing more than a decade ago. This 2008 study followed 8 patients for for 2 years after receiving an average of 90 million CD34 cells directly to the spinal cord with no serious adverse events. The patients reported improvements in scores using various scales (ASIA, Barthel, Frankel, Ashworth), and changes to the spinal cord were observed on MRI. The authors note that they continued on to safely treat 52 more patients. While the authors did not quantify the number of mesenchymal stem cells (MSCs) in the aspirate concentrate, this is one of the earlier studies that paved the way for current research with MSCs.

Cell Transplant. 2008;17(12):1277-93. https://doi.org/10.3727/096368908787648074

Administration of autologous bone marrow stem cells into spinal cord injury patients via multiple routes is safe and improves their quality of life: comprehensive case studies.

Geffner LF, Santacruz P, Izurieta M, Flor L, Maldonado B, Auad AH, Montenegro X, Gonzalez R, Silva F.

Abstract

Presently, there is no cure or effective treatment for spinal cord injury (SCI). Studies in SCI patients have shown that for a treatment to be effective it must primarily improve their quality of life. Numerous studies have shown that stem cells represent an alternative treatment for various disorders and have shown promise in several disease/trauma states. For instance, the use of autologous CD34+ stem cells has been shown to ameliorate symptoms of several disorders such as leukemia, cardiomyopathy, diabetes, and several autoimmune diseases, including multiple sclerosis. For the first time, we report eight case studies of SCI (four acute, four chronic) with approximately 2 years of follow-up that were administered bone marrow stem cells (BMSCs) via multiple routes: directly into the spinal cord, directly into the spinal canal, and intravenous. Magnetic resonance imaging illustrated morphological changes in the spinal cord of some of the patients following BMSCs administration. Comprehensive evaluations demonstrate improvements in ASIA, Barthel (quality of life), Frankel, and Ashworth scoring. Moreover, in order to assess bladder function, we designed a simple numerical clinical scoring system that demonstrates significant changes in bladder function following BMSCs administration. To date, we have administration BMSCs into 52 patients with SCI and have had no tumor formations, no cases of infection or increased pain, and few instances of minor adverse events. These studies demonstrate that BMSCs administration via multiple routes is feasible, safe, and may improve the quality of life for patients living with SCI.

PMID: 19364066

MSCs: A step forward for mitochondrial diseases

Posted on April 2, 2019 Written by nhriordan Leave a Comment

Mitochondria are extremely important for cells, as they produce the energy they need to carry out their tasks in a normal, healthy body. So when mitochondria can’t or won’t function as they are supposed to, serious conditions or diseases can develop.

This 2018 study from Canada shows that human mesenchymal stem cells can interact with diseased mitochondria and correct or influence their activity in the cells. To demonstrate this, the authors cultured human MSC with human mitochondria extracted from patients with mitochondrial malfunctions. The authors also injected MSC into mice with known mitochondrial defects and studied their mitochondrial response.

This is a really exciting breakthrough for mitochondrial diseases, as patients suffering from these conditions could potentially be treated with MSC in future studies.

Front Physiol. 2018 Nov 13;9:1572. doi: 10.3389/fphys.2018.01572.

Mesenchymal Stem Cells Shift Mitochondrial Dynamics and Enhance Oxidative Phosphorylation in Recipient Cells.

Newell C, Sabouny R, Hittel DS, Shutt TE, Khan A, Klein MS, Shearer J.

Abstract

Mesenchymal stem cells (MSCs) are the most commonly used cells in tissue engineering and regenerative medicine. MSCs can promote host tissue repair through several different mechanisms including donor cell engraftment, release of cell signaling factors, and the transfer of healthy organelles to the host. In the present study, we examine the specific impacts of MSCs on mitochondrial morphology and function in host tissues. Employing in vitro cell culture of inherited mitochondrial disease and an in vivo animal experimental model of low-grade inflammation (high fat feeding), we show human-derived MSCs to alter mitochondrial function. MSC co-culture with skin fibroblasts from mitochondrial disease patients rescued aberrant mitochondrial morphology from a fission state to a more fused appearance indicating an effect of MSC co-culture on host cell mitochondrial network formation. In vivo experiments confirmed mitochondrial abundance and mitochondrial oxygen consumption rates were elevated in host tissues following MSC treatment. Furthermore, microarray profiling identified 226 genes with differential expression in the liver of animals treated with MSC, with cellular signaling, and actin cytoskeleton regulation as key upregulated processes. Collectively, our data indicate that MSC therapy rescues impaired mitochondrial morphology, enhances host metabolic capacity, and induces widespread host gene shifting. These results highlight the potential of MSCs to modulate mitochondria in both inherited and pathological disease states.

PMID: 30555336 PMCID: PMC6282049

Early treatment with BMMSC for spinal cord injury results in long-term benefits

Posted on March 18, 2019 Written by nhriordan Leave a Comment

The earlier, the better: in spinal cord injuries, treatment with mesenchymal stem cells may make a difference if applied soon after trauma. In this 2015 Polish case report, a 15 year old girl was treated with bone marrow MSC just 21 days after injury. She was paraplegic at the start of treatment (able to move her arms, but no control over trunk, legs, or bowels). She received 154 million BMMSC, spaced over every 3-4 months over the course of 2 years. At the end of treatment, the patient was able to stand, regained control over her trunk and sensation in her legs and bowels.

Cell Transplant. 2015;24(4):661-72. doi: 10.3727/096368915X687796. Epub 2015 Mar 24.

Continuous improvement after multiple mesenchymal stem cell transplantations in a patient with complete spinal cord injury.

Jarocha D, Milczarek O, Wedrychowicz A, Kwiatkowski S, Majka M.

Abstract

Interruption of spinal cord (SC) continuity leads to functional loss below the lesion level. The purpose of this study was to evaluate the safety and efficacy of bone marrow nucleated cell (BMNC) and multiple mesenchymal stem cell (MSC) transplantations in spinal cord injury (SCI). A patient with total SC interruption at the Th2-3 level underwent experimental therapy with BMNC and MSC transplantations followed with intensive neurorehabilitation treatment. At admission, 6 h after SCI, the patient was scored ASIA A, had a Th1 sensation level, paraplegia with sphincter palsy, and was without the ability to control trunk movement. Neurophysiology examination showed bilateral axonal damage to the motor and sensory neural fibers with no motor unit potentials or peripheral motor nerve conduction in the lower extremities. The standard therapy had been applied and had not produced any positive results. The patient was treated with autologous BMNCs injected intravenously (3.2×10(9)) and intrathecally (0.5×10(9)) 10 weeks after the SCI and with five rounds of MSCs every 3-4 months (1.3-3.65×10(7)) administered via lumbar puncture. Total number of transplanted MSC cells during the course of treatment was 1.54×10(8). There were no complications related to transplantations and no side effects related to the therapy during 2 years of treatment. The ASIA score improved from A to C/D (from 112 to 231 points). The sensation level expanded from Th1 to L3-4, and the patient’s ability to control the body trunk was fully restored. Bladder filling sensation, bladder control, and anal sensation were also restored. Muscle strength in the left lower extremities improved from plegia to deep paresis (1 on the Lovett scale). The patient’s ability to move lower extremities against gravity supported by the movements in quadriceps was restored. The patient gained the ability to stand in a standing frame and was able to walk with the support of hip and knee ortheses. Magnetic resonance imaging (MRI) revealed that at the Th2/Th3 level, where the hemorrhagic necrosis was initially observed, small tissue structures appeared. Our results suggest that repeated intrathecal infusions of MSCs might have the potential to produce clinically meaningful improvements for SCI patients.

PMID: 5807231