Regenerative Therapy Research
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Stem Cell Therapy Research
Long Term Studies
Stem Cell Therapy Published Research Abstracts
Treatment of lumbar degenerative disc disease-associated radicular pain with culture-expanded autologous mesenchymal stem cells: a pilot study on safety and efficacy.
Degenerative disc disease (DDD) is a common cause of lower back pain with radicular symptoms and has a significant socioeconomic impact given the associated disability. Limited effective conservative therapeutic options result in many turning to surgical alternatives for management, which vary in the rate of success and also carry an increased risk of morbidity and mortality associated with the procedures. Several animal based studies and a few human pilot studies have demonstrated safety and suggest efficacy in the treatment of DDD with mesenchymal stem cells (MSCs). The use of bone marrow-derived MSCs for the treatment of DDD is promising and in the present study we report on the safety and efficacy findings from a registry based proof of concept study using a percutaneous intradiscal injection of cultured MSCs for the management of DDD with associated radicular symptoms.
Thirty-three patients with lower back pain and disc degeneration with a posterior disc bulge diagnosed on magnetic resonance imaging (MRI) met the inclusion criteria and were treated with culture-expanded, autologous, bone marrow-derived MSCs. Prospective registry data was obtained at multiple time intervals up to 6 years post-treatment. Collected outcomes included numeric pain score (NPS), a modified single assessment numeric evaluation (SANE) rating, functional rating index (FRI), measurement of the intervertebral disc posterior dimension, and adverse events.
Three patients reported pain related to procedure that resolved. There were no serious adverse events (i.e. death, infection, or tumor) associated with the procedure. NPS change scores relative to baseline were significant at 3, 36, 48, 60, and 72 months post-treatment. The average modified SANE ratings showed a mean improvement of 60% at 3 years post-treatment. FRI post-treatment change score averages exceeded the minimal clinically important difference at all time points except 12 months. Twenty of the patients treated underwent post-treatment MRI and 85% had a reduction in disc bulge size, with an average reduction size of 23% post-treatment.
Patients treated with autologous cultured MSCs for lower back pain with radicular symptoms in the setting of DDD reported minor adverse events and significant improvements in pain, function, and overall subjective improvement through 6 years of follow-up.
Abstract: The use of stem cells in orthopedics has been researched for many years, with robust animal data that show efficacy in cartilage healing, tendon repair, and intervertebral disk treatment. Early clinical data are also just starting to be published, and these results are encouraging. Safety data in large case series, some that lasted for many years, have also been published. The field of tissue engineering with stem cells in musculoskeletal impairments has the potential to reduce morbidity and improve clinical outcomes. The regulatory environment for this area of medicine is still developing.
Copyright © 2014 American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved. PMID: 24439149
Percutaneous injection of autologous, culture-expanded mesenchymal stem cells into carpometacarpal hand joints: a case series with an untreated comparison group.
Centeno CJ, D Freeman M.
BACKGROUND: Mesenchymal stem cells (MSCs) show promising clinical potential as multipotent therapeutic agents in regenerative medicine, including a number of orthopedic applications. Objective: To study the possible value of MSC’s injected intra-articular in patients with carpometecarpal (CMC) joint and hand osteoarthritis (OA).
METHODS: This is a prospective, case series with an untreated control that was obtained through a convenience sample. Patients underwent a bone marrow aspiration with isolation and culture expansion of MSC’s using a serum free, autologous platelet lysate. Autologous MSC’s were injected intra-articular utilizing imaging guidance. Percentage improvement, functional and visual analog scale data was collected via survey at pre-procedure, 3 months, 6 months, and annually.
RESULTS: Six OA patients and four controls were recruited. The mean reported pain relief was significantly higher +60% in the thumb OA group (n=6, p=.032) than in the control -18.75% (n=4). The average time reporting was 11.83 +/- 5.70 months and 9.55 +/- 6.49 months for both groups, respectively. On average, a greater than 30% reduction were observed in all VAS scale metrics (n=5), average reporting time was 13 +/-5.52 months. The majority of patients (66.7%, n=6) reported an increase in both strength and range of motion, average reporting time was 11.83 +/- 5.7 months. No complications were reported.
CONCLUSIONS:Percutaneous implantation of cultured MSCs into the carpometecarpal joint was associated with patient reported improvement in pain and function that was not seen in an untreated control. In addition, all patients within this small case series reported no complications.
Regeneration of meniscus cartilage in a knee treated with percutaneously implanted autologous mesenchymal stem cells.
Centeno CJ, Busse D, Kisiday J, Keohan C, Freeman M, Karli D.
Regenerative Sciences Inc, Centeno-Schultz Clinic, Westminster, CO 80020, USA.
Mesenchymal stem cells are pluripotent cells found in multiple human tissues including bone marrow, synovial tissues, and adipose tissues. They have been shown to differentiate into bone, cartilage, muscle, and adipose tissue and represent a possible promising new therapy in regenerative medicine. Because of their multi-potent capabilities, mesenchymal stem cell (MSC) lineages have been used successfully in animal models to regenerate articular cartilage and in human models to regenerate bone. The regeneration of articular cartilage via percutaneous introduction of mesenchymal stem cells (MSC’s) is a topic of significant scientific and therapeutic interest. Current treatment for cartilage damage in osteoarthritis focuses on surgical interventions such as arthroscopic debridement, microfracture, and cartilage grafting/transplant. These procedures have proven to be less effective than hoped, are invasive, and often entail a prolonged recovery time. We hypothesize that autologous mesenchymal stem cells can be harvested from the iliac crest, expanded using the patient’s own growth factors from platelet lysate, then successfully implanted to increase cartilage volume in an adult human knee. We present a review highlighting the developments in cellular and regenerative medicine in the arena mesenchymal stem cell therapy, as well as a case of successful harvest, expansion, and transplant of autologous mesenchymal stem cells into an adult human knee that resulted in an increase in meniscal cartilage volume.
Clinical feasibility of umbilical cord tissue-derived mesenchymal stem cells in the treatment of multiple sclerosis
Riordan NH1,2, Morales I3, Fernández G4, Allen N5, Fearnot NE5, Leckrone ME6, Markovich DJ5, Mansfield D5, Avila D3, Patel AN7, Kesari S8, Paz Rodriguez J4.
Multiple sclerosis (MS) is a progressively debilitating neurological condition in which the immune system abnormally erodes the myelin sheath insulating the nerves. Mesenchymal stem cells (MSC) have been used in the last decade to safely treat certain immune and inflammatory conditions.
A safety and feasibility study was completed on the use of umbilical cord MSC (UCMSC) as a treatment for MS. In this 1-year study, consenting subjects received seven intravenous infusions of 20 × 106 UCMSC over 7 days. Efficacy was assessed at baseline, 1 month and 1 year after treatment, including magnetic resonance imaging (MRI) scans, Kurtzke Expanded Disability Status Scale (EDSS), Scripps Neurological Rating Scale, Nine-Hole Peg Test, 25-Foot Walk Test, and RAND Short Form-36 quality of life questionnaire.
Twenty subjects were enrolled in this study. No serious adverse events were reported. Of the mild AEs denoted as possibly related to treatment, most were headache or fatigue. Symptom improvements were most notable 1 month after treatment. Improvements were seen in EDSS scores (p < 0.03), as well as in bladder, bowel, and sexual dysfunction (p < 0.01), in non-dominant hand average scores (p < 0.01), in walk times (p < 0.02) and general perspective of a positive health change and improved quality of life. MRI scans of the brain and the cervical spinal cord showed inactive lesions in 15/18 (83.3%) subjects after 1 year.
Treatment with UCMSC intravenous infusions for subjects with MS is safe, and potential therapeutic benefits should be further investigated. Trial registration ClinicalTrials.gov NCT02034188. Registered Jan 13, 2014. https://clinicaltrials.gov/ct2/show/NCT02034188.
Intraperitoneal infusion of mesenchymal stem cell attenuates severity of collagen antibody induced arthritis
Nam Y, Jung SM, Rim YA, Jung H, Lee K, Park N, Kim J, Jang Y, Park YB, Park SH, Ju JH
It is unclear how systemic administration of mesenchymal stem cells (MSCs) controls local inflammation. The aim of this study was to evaluate the therapeutic effects of human MSCs on inflammatory arthritis and to identify the underlying mechanisms. Mice with collagen antibody-induced arthritis (CAIA) received two intraperitoneal injections of human bone marrow-derived MSCs. The clinical and histological features of injected CAIA were then compared with those of non-injected mice. The effect of MSCs on induction of regulatory T cells was examined both in vitro and in vivo. We also examined multiple cytokines secreted by peritoneal mononuclear cells, along with migration of MSCs in the presence of stromal cell-derived factor-1 alpha (SDF-1α) and/or regulated on activation, normal T cell expressed and secreted (RANTES). Sections of CAIA mouse joints and spleen were stained for human anti-nuclear antibodies (ANAs) to confirm migration of injected human MSCs. The results showed that MSCs alleviated the clinical and histological signs of synovitis in CAIA mice. Peritoneal lavage cells from mice treated with MSCs expressed higher levels of SDF-1α and RANTES than those from mice not treated with MSCs. MSC migration was more prevalent in the presence of SDF-1α and/or RANTES. MSCs induced CD4+ T cells to differentiate into regulatory T cells in vitro, and expression of FOXP3 mRNA was upregulated in the forepaws of MSC-treated CAIA mice. Synovial and splenic tissues from CAIA mice receiving human MSCs were positive for human ANA, suggesting recruitment of MSCs. Taken together, these results suggest that MSCs migrate into inflamed tissues and directly induce the differentiation of CD4+ T cells into regulatory T cells, which then suppress inflammation. Thus, systemic administration of MSCs may be a therapeutic option for rheumatoid arthritis.
Autologous Adipose-Derived Mesenchymal Stromal Cells for the Treatment of Psoriasis Vulgaris and Psoriatic Arthritis: A Case Report
De Jesus MM, Santiago JS, Trinidad CV, See ME, Semon KR, Fernandez MO Jr, Chung F
Psoriasis is a dermatologic disease of immune origins with no definitive cure. We report the Makati Medical Center experience of utilizing autologous mesenchymal stromal cells (MSCs) for one patient with psoriasis vulgaris (PV) and another with psoriatic arthritis (PA). Patients were educated and gave informed consent, according to the principles of the Declaration of Helsinki. The protocol was approved by the Cellular Transplantation Ethics Committee of the Makati Medical Center. Autologous MSCs were cultured from lipoaspirate and expanded in a clean room class 100 facility (Cellular Therapeutics Center, Makati Medical Center). MSCs were infused intravenously at a dose of 0.5-3.1 million cells/kg after complying with quality control parameters. Psoriasis area and severity index (PASI) evaluations were conducted by third-party dermatologists. The PA patient, who was previously unresponsive to standard treatment modalities, demonstrated a decrease in PASI (from 21.6 to 9.0, mild state after two infusions). No improvements were noted in joint pain until further treatment with etanercept and infliximab. The PV patient, who was previously dependent on methotrexate, showed a decrease in PASI from 24.0 to 8.3 after three infusions; this clinical improvement was sustained for 292 days (9.7 months) without methotrexate. The PV patient illustrated a marginal reduction in serum tumor necrosis factor-α (TNF-α), while significant (3.5- to 5-fold) decreases in reactive oxygen species (ROS) activity were noted. The ROS levels correlated with the clinical improvement of the PV patient. No serious adverse events were noted for either patient as a result of MSC infusions. This report demonstrates safe and tolerable transplantation of autologous MSCs for the treatment of psoriasis and warrants large clinical studies to investigate the long-term safety and efficacy of this approach.
Mesenchymal stromal cells-derived matrix Gla protein contribute to the alleviation of experimental colitis
Feng Y, Liao Y, Huang W, Lai X, Luo J, Du C, Lin J, Zhang Z, Qiu D, Liu Q, Shen H, Xiang AP, Zhang Q
Crohn’s disease (CD) is a chronic inflammatory bowel disease that is difficult to treat. However, previous preclinical and clinical studies have shown that mesenchymal stromal cells (MSCs) are a promising therapeutic approach, whereas the exact underlying molecular mechanisms of MSCs in treating CD remain unclear. Furthermore, the heterogeneity of MSCs, as well as the in vivo microenvironments may influence the therapeutic efficacy. In our previous study, we found that a subpopulation of mouse MSCs with a high expression of matrix Gla protein (MGP), one of the members of vitamin K-dependent protein family, possessed better immunoregulatory properties. Therefore, in this study we investigate whether the abundant MSCs-derived MGP participate in the therapeutic mechanisms for MSCs treating CD. Obvious suppression of cell proliferation and cytokine production in T cells were observed in vitro through MSCs-derived MGP. Moreover, MGP alleviated the clinical and histopathological severity of colonic inflammation in mouse experimental colitis models to a remarkable degree. Our results indicate that MGP might be a novel important mediator of MSCs-mediated immunomodulation in treating CD.
Platlet-Rich Plasma Therapy Research
IV Nutritional Therapy Research
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