Research
Stem cell therapies in tendon-bone healing
Abstract
Tendon-bone insertion injuries such as rotator cuff and anterior cruciate ligament injuries are currently highly common and severe. The key method of treating this kind of injury is the reconstruction operation. The success of this reconstructive process depends on the ability of the graft to incorporate into the bone. Recently, there has been substantial discussion about how to enhance the integration of tendon and bone through biological methods. Stem cells like bone marrow mesenchymal stem cells (MSCs), tendon stem/progenitor cells, synovium-derived MSCs, adipose-derived stem cells, or periosteum-derived periosteal stem cells can self-regenerate and potentially differentiate into different cell types, which have been widely used in tissue repair and regeneration. Thus, we concentrate in this review on the current circumstances of tendon-bone healing using stem cell therapy.
Intratendinous Injection of AutologousAdipose Tissue-Derived MesenchymalStem Cells for the Treatment of RotatorCuff Disease: A First-In-Human Trial
ABSTRACT
Despite relatively good results of current symptomatictreatments for rotator cuff disease, there has been an unmetneed for fundamental treatments to halt or reverse the progressof disease. The purpose of this study was to assess the safety andefficacy of intratendinous injection of autologous adiposetissue-derived mesenchymal stem cells (AD MSCs) in patientswith rotator cuff disease. The first part of the study consists ofthree dose-escalation cohorts; the low- (1.0 × 10 cells), mid- (5.0× 10), and high-dose (1.0 × 10) groups with three patients eachfor the evaluation of the safety and tolerability. The second partincluded nine patients receiving the high-dose for theevaluation of the exploratory efficacy. The primary outcomeswere the safety and the shoulder pain and disability index(SPADI). Secondary outcomes included clinical, radiological, andarthroscopic evaluations. Twenty patients were enrolled in thestudy, and two patients were excluded. Intratendinous injectionof AD MSCs was not associated with adverse events. Itsignificantly decreased the SPADI scores by 80% and 77% in themid- and high-dose groups, respectively. Shoulder pain wassignificantly alleviated by 71% in the high-dose group. Magneticresonance imaging examination showed that volume of thebursal-side defect significantly decreased by 90% in the high-dose group. Arthroscopic examination demonstrated thatvolume of the articular- and bursal-side defects decreased by83% and 90% in the mid- and high-dose groups, respectively.Intratendinous injection of autologous AD MSCs in patient witha partial-thickness rotator cuff tear did not cause adverse events,but improved shoulder function, and relieved pain throughregeneration of rotator cuff tendon.
Mesenchymal Stem Cells From a Hypoxic Culture Can Improve Rotator Cuff Tear Repair
Abstract
A rotator cuff tear is an age-related common cause of pain and disability. Studies including our previously published ones have demonstrated that mesenchymal stem cells cultured under hypoxic conditions [hypoxic multipotent stromal cells (MSCs)] facilitate the retention of transplanted cells and promote wound healing. However, there are very few, if any, reports targeting the punctured supraspinatus tendons to create more or equally serous wounds as age-related tears of rotator cuff. It remains to be determined whether transplantation of bone-marrow-derived hypoxic MSCs into the punctured supraspinatus tendon improves tendon repair and, when combined with ultrasound-guided delivery, could be used for future clinical applications. In this study, we used a total of 33 Sprague-Dawley rats in different groups for normal no-punched control, hypoxic MSC treatment, nontreated vehicle control, and MSC preparation, and then evaluated treatment outcomes by biomechanical testing and histological analysis. We found that the ultimate failure load of the hypoxic MSC-treated group was close to that of the normal tendon and significantly greater than that of the nontreated vehicle control group. In vivo tracking of cells labeled with superparamagnetic iron oxide (SPIO) nanoparticles revealed an enhanced retention of transplanted cells at the tear site. Our study demonstrates that hypoxic MSCs improve rotator cuff tear repair in a rat model.
Phase I trial of hES cell-derived dopaminergic neurons for Parkinson’s disease
Parkinson’s disease is a progressive neurodegenerative condition with a considerable health and economic burden1. It is characterized by the loss of midbrain dopaminergic neurons and a diminished response to symptomatic medical or surgical therapy as the disease progresses. Cell therapy aims to replenish lost dopaminergic neurons and their striatal projections by intrastriatal grafting. Here, we report the results of an open-label phase I clinical trial (NCT04802733) of an investigational cryopreserved, off-the-shelf dopaminergic neuron progenitor cell product (bemdaneprocel) derived from human embryonic stem (hES) cells and grafted bilaterally into the putamen of patients with Parkinson’s disease. Twelve patients were enrolled sequentially in two cohorts—a low-dose (0.9 million cells, n = 5) and a high-dose (2.7 million cells, n = 7) cohort—and all of the participants received one year of immunosuppression. The trial achieved its primary objectives of safety and tolerability one year after transplantation, with no adverse events related to the cell product. At 18 months after grafting, putaminal 18Fluoro-DOPA positron emission tomography uptake increased, indicating graft survival. Secondary and exploratory clinical outcomes showed improvement or stability, including improvement in the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III OFF scores by an average of 23 points in the high-dose cohort. There were no graft-induced dyskinesias. These data demonstrate safety and support future definitive clinical studies.
Repeated Intravenous Administration of Mesenchymal Stromal Cells Produces Cumulative Beneficial Effects in Chronic Ischemic Cardiomyopathy
Cell therapy is a potentially useful approach to treating heart failure (HF) secondary to chronic ischemic cardiomyopathy (ischemic HF). Despite controversy, the preclinical data in the field of cell therapy are clear: Although transplanted cells do not regenerate cardiomyocytes, preclinical studies have consistently shown that they improve cardiac performance. Bone marrow–derived mesenchymal stromal cells (MSCs) are among the most promising cell types in the preclinical arena1 and for patients with ischemic HF.
The field of cell therapy is evolving rapidly. The fundamental shift has been the recognition that all cell types fail to engraft in the heart and instead work via paracrine mechanisms. This concept has 2 corollaries: (1) because transplanted cells do not persist in the heart for more than a few weeks, giving repeated doses seems logical; and (2) because cells work by releasing factors in the environment, intravenous (IV) therapy may also be effective by enabling systemic release of these factors.
Parkinson’s Patients Say Their Symptoms Eased After Receiving Millions of New Brain Cells
Grabbing a coffee cup seems easy. But you need to be able to move your hand, stretch it out, and keep it steady.
These movements are difficult for people with Parkinson’s disease. The disorder eats away at brain cells—called dopamine neurons—that control movement and emotion. Symptoms begin with tremors. Then muscles lock up. Eventually, the disease makes walking and sleeping difficult. Thinking gets harder, and as neurons die, people lose their concentration and memory.
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Potential role of stem cells for neuropathic pain disorders
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Chronic neuropathic pain is estimated to be on the rise, particularly with the expected increase in patients with diabetes within the US. Diabetic and nondiabetic patients were surveyed for sick days from
work due to neuropathic pain; approximately two-thirds of these patients were found to consistently be taking days from work, and only one-fifth of those were satisfied with their current therapy.8,24 Unlike nociceptive pain (tissue injury induced), neuropathic pain is specific to injury of either the central or peripheral nervous system and can be a combination of both. For this reason, several diseases manifest with neuropathy including SCI, stroke, multiple sclerosis, diabetes, infectious related, nutrient deficient,
immune related, and oncological. Interestingly, adjuvant therapies for these disorders including chemotherapy and radiation therapy can also lead to chronic neuropathy. Treatments have largely depended on anticonvulsants and antidepressants because of their analgesic effects; however, the nature of neuropathic pain is its chronicity and as such often becomes recalcitrant to these pharmacological strategies. Intractable neuropathic pain has gained increasing awareness due to its prevalence and the technological advancements in surgical neuromodulation. Electrical stimulation via spinal cord, peripheral nerve, and deep brain targeting has begun to show some early efficacy. 18 To date, chronic neuropathic pain is largely considered a heterogeneous pain syndrome that remains with limited efficacious treatment modalities. Also, there is no treatment strategy that is effective for pain management while promoting nervous system repair.
Anti-Inflammatory Mesenchymal Stem Cells (MSC2)Attenuate Symptoms of Painful Diabetic PeripheralNeuropathy
ABSTRACT
Mesenchymal stem cells (MSCs) are very attractive candidates in cell-based strategies that target
inflammatory diseases. Preclinical animal studies and many clinical trials have demonstrated that
human MSCs can be safely administered and that they modify the inflammatory process in the
targeted injured tissue. Our laboratory developed a novel method that optimizes the anti-inflammatory effects of MSCs. We termed the cells prepared by this method MSC2. In this study, we
determined the effects of MSC2-based therapies on an inflammation-linked painful diabetic peripheral neuropathy (pDPN) mouse model. Streptozotocin-induced diabetic mice were treated with
conventionally prepared MSCs, MSC2, or vehicle at three specific time points. Prior to each treatment, responses to radiant heat (Hargreaves) and mechanical stimuli (von Frey) were measured.
Blood serum from each animal was collected at the end of the study to compare levels of inflammatory markers between the treatment groups. We observed that MSC2-treated mice had significant
improvement in behavioral assays compared with the vehicle and MSC groups, and moreover these
responses did not differ from the observations seen in the healthy wild-type control group. Mice
treated with conventional MSCs showed significant improvement in the radiant heat assay, but not
in the von Frey test. Additionally, mice treated with MSC2 had decreased serum levels in many
proinflammatory cytokines compared with the values measured in the MSC- or vehicle-treated
groups. These findings indicate that MSC2-based therapy is a new anti-inflammatory treatment to
consider in the management of pDPN. STEM CELLS TRANSLATIONAL MEDICINE 2012;1:
557–565
A preliminary report on stem cell therapy for neuropathic pain in humans
Objective:
Mesenchymal stem cells (MSCs) have been shown in animal models to attenuate
chronic neuropathic pain. This preliminary study investigated if: i) injections of autologous
MSCs can reduce human neuropathic pain and ii) evaluate the safety of the procedure.
Methods:
Ten subjects with symptoms of neuropathic trigeminal pain underwent liposuction.
The lipoaspirate was digested with collagenase and washed with saline three times. Following
centrifugation, the stromal vascular fraction was resuspended in saline, and then transferred to
syringes for local injections into the pain fields. Outcome measures at 6 months assessed reduction in: i) pain intensity measured by standard numerical rating scale from 0–10 and ii) daily
dosage requirements of antineuropathic pain medication.
Results:
Subjects were all female (mean age 55.3 years ± standard deviation [SD] 14.67; range
27–80 years) with pain symptoms lasting from 4 months to 6 years and 5 months. Lipoaspirate
collection ranged from 102–214 g with total cell numbers injected from 33 million to 162 million
cells. Cell viability was 62%–91%. There were no systemic or local tissue side effects from the
stem cell therapy (n=41 oral and facial injection sites). Clinical pain outcomes showed that at 6
months, 5/9 subjects had reduced both pain intensity scores and use of antineuropathic medication. The mean pain score pre-treatment was 7.5 (SD 1.58) and at 6 months had decreased to 4.3
(SD 3.28), P=0.018, Wilcoxon signed-rank test. Antineuropathic pain medication use showed
5/9 subjects reduced their need for medication (gabapentin, P=0.053, Student’s t-test).
Conclusion: This preliminary open-labeled study showed autologous administration of stem
cells for neuropathic trigeminal pain significantly reduced pain intensity at 6 months and is a
safe and well tolerated intervention.
Keywords: adipose, stem cells, neuropathic, orofacial, trigeminal
Intravenous neural stem cells abolish nociceptive hypersensitivity and trigger nerve regeneration in experimental neuropathy
A nonphysiological repair of the lesioned nerve leading to the formation of neurinomas, altered nerve
conduction, and spontaneous firing is considered the main cause of the events underlying neuropathic
pain. It was investigated whether neural stem cell (NSCs) administration could lead to a physiological
nerve repair, thus to a reduction of neuropathic pain symptoms such as hyperalgesia and allodynia in
a well-established model of this pain (sciatic nerve chronic constriction injury [CCI]). Moreover, since
we and others showed that the peripheral nerve lesion starts a cascade of neuroinflammation-related
events that may maintain and worsen the original lesion, the effect of NSCs on sciatic nerve pro- and antiinflammatory cytokines in CCI mice was investigated. NSCs injected intravenously, when the pathology
was already established, induced a significant reduction in allodynia and hyperalgesia already 3 days
after administration, demonstrating a therapeutic effect that lasted for at least 28 days. Responses changed with the number of administered NSCs, and the effect on hyperalgesia could be boosted by a new NSC
administration. Treatment significantly decreased proinflammatory, activated antiinflammatory cytokines in the sciatic nerve, and reduced spinal cord Fos expression in laminae I-VI. Moreover, in NSC-treated animals, a reparative process and an improvement of nerve morphology is present at a later time.
Since NSC effect on pain symptoms preceded nerve repair and was maintained after cells had disappeared
from the lesion site, we suggest that regenerative, behavioral, and immune NSC effects are largely due to microenvironmental changes they might induce at the lesion site