Research Selection: Curated Abstracts by Dr. Pruski

View a selection of research abstracts curated by Dr. Jeffrey Pruski himself.

Injectable Amniotic Membrane/Umbilical Cord Particulate for Knee Osteoarthritis: A Prospective, Single-Center Pilot Study

Objective: To evaluate the short-term safety and effectiveness of amniotic membrane/umbilical cord particulate (AMUC) in managing pain in patients with various severities of knee osteoarthritis (OA).

Design: Single-center, prospective, investigator-initiated pilot study. Setting. Private practice. Subjects. A total of 20 knee OA patients aged 18 years were enrolled with pain >40 mm, as determined by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)–A.

Methods: Patients received an ultrasound-guided, intra-articular injection of 50 mg of AMUC particulate reconstituted in 2 mL of preservative-free saline. All patients were then monitored at six weeks, 12 weeks, and 24 weeks postinjection. Patients who did not show >30% reduction in pain received a second injection of AMUC at six weeks. WOMAC, Patient Global Assessment, medication usage, and magnetic resonance imaging (MRI) were assessed.

Results: Knee OA pain significantly decreased from 74.3 6 17.2 at baseline to 45.0 6 25.4 at six weeks (P < 0.01), 35.4 6 26.6 at 12 weeks (P < 0.001), and 37.4 6 26.7 at 24 weeks (P < 0.001). This pain reduction was associated with a significant improvement in physical function (WOMAC-C) at all time points (P < 0.05) and stiffness (WOMAC-B) at 12 weeks (P ¼ 0.01). Eleven patients received a second injection, which was significantly correlated with body mass index >30 kg/m2 (P ¼ 0.025). MRI evaluation of the overall population revealed an improvement in the severity of bone marrow lesions in seven patients. No adverse events were observed.

Conclusions: AMUC particulate injection relieved pain and improved physical function in patients with symptomatic knee OA.

Castellanos, R., & Tighe, S. (2019). Injectable Amniotic Membrane/Umbilical Cord Particulate for Knee Osteoarthritis: A Prospective, Single-Center Pilot Study. Pain Medicine, 20(11), 2283–2291. doi: 10.1093/pm/pnz143

HC-HA/PTX3 Purified From Amniotic Membrane as Novel Regenerative Matrix: Insight Into Relationship Between Inflammation and Regeneration

PURPOSE: Human limbal palisade of Vogt is an ideal model for studying and practicing regenerative medicine due to their accessibility. Nonresolving inflammation is a common manifestation of limbal stem cell deficiency, which is the major cause of corneal blindness, and presents as a threat to the success of transplanted limbal epithelial stem cells. Clinical studies have shown that the efficacy of transplantation of limbal epithelial stem cells can be augmented by transplantation of cryopreserved human amniotic membrane (AM), which exerts anti-inflammatory, antiscarring, and antiangiogenic action to promote wound healing. 

METHODS: Review of published data to determine the molecular action mechanism explaining how AM exerts the aforementioned therapeutic actions.

RESULTS: From the water-soluble extract of cryopreserved AM, we have biochemically purified one novel matrix component termed heavy chain (HC)-hyaluronan (HA)/pentraxin 3 (PTX3) as the key relevant tissue characteristic responsible for the aforementioned AM’s efficacy. Heavy chain–HA is a complex formed by a covalent linkage between HA and HC1 of inter-atrypsin inhibitor (IaI) by tumor necrosis factor-stimulated gene-6 (TSG-6). This complex may then be tightly associated with PTX3 to form HC-HA/PTX3 complex. Besides exerting an antiinflammatory, antiscarring, and antiangiogenic effects, HC-HA/PTX3 complex also uniquely maintains limbal niche cells to support the quiescence of limbal epithelial stem cells.

CONCLUSIONS: We envision that HC-HA/PTX3 purified from AM can be used as a unique substrate to refine ex vivo expansion of limbal epithelial stem cells by maintaining stem cell quiescence, self-renewal and fate decision. Furthermore, it can also be deployed as a platform to launch new therapeutics in regenerative medicine by mitigating nonresolving inflammation and reinforcing the well-being of stem cell niche.

Tseng, S. C. G. (2016). HC-HA/PTX3 Purified From Amniotic Membrane as Novel Regenerative Matrix: Insight Into Relationship Between Inflammation and Regeneration. Investigative Opthalmology & Visual Science, 57(5). doi: 10.1167/iovs.15-17637

Intramuscular administration potentiates extended dwell time of mesenchymal stromal cells compared to other routes

Background: Mesenchymal stromal cells (MSCs) offer great potential for diverse clinical applications. However, conventional systemic infusion of MSCs limits their therapeutic benefit, since intravenously (IV) infused cells become entrapped in the lungs where their dwell time is short. 

Methods: To explore possible alternatives to IV infusion, we used in vivo optical imaging to track the bio-distribution and survival of 1 million bioluminescent MSCs administered IV, intraperitoneally (IP), subcutaneously (SC) and intramuscularly (IM) in healthy athymic mice. 

Results: IV-infused MSCs were undetectable within days of administration, whereas MSCs implanted IP or SC were only detected for 3 to 4 weeks. In contrast, MSCs sourced from human umbilical cord matrix or bone marrow survived more than 5 months in situ when administered IM. Longterm survival was optimally achieved using low passage cells delivered IM. However, MSCs could undergo approximately 30 doublings before their dwell time was compromised. Cryo-preserved MSCs administered IM promptly after thaw were predominantly cleared after 3 days, whereas equivalent cells cultured overnight prior to implantation survived more than 3 months. 

Discussion: The IM route supports prolonged cell survival of both neo-natal and adult-derived MSCs, although short-term MSC survival was comparable between all tested routes up to day 3. IM implantation presents a useful alternative to achieve clinical benefits from prolonged MSC dwell time at a homeostatic implant site and is a minimally invasive delivery route suitable for many applications. However, optimized thaw protocols that restore full biological potential of cryo-preserved MSC therapies prior to implantation must be developed.

Braid, L. R., Wood, C. A., Wiese, D. M., & Ford, B. N. (2018). Intramuscular administration potentiates extended dwell time of mesenchymal stromal cells compared to other routes. Cytotherapy, 20(2), 232–244. doi: 10.1016/j.jcyt.2017.09.013

A Randomized Controlled Single-Blind Study Demonstrating Superiority of Amniotic Suspension Allograft Injection Over Hyaluronic Acid and Saline Control for Modification of Knee Osteoarthritis Symptoms

Placental-derived tissues are a known source of anti-inflammatory and immune modulating factors. Published pilot data on amniotic suspension allograft (ASA) for the treatment of osteoarthritis (OA) demonstrated safety and trends for improved pain and function. A multicenter randomized controlled trial was designed to evaluate the efficacy of symptom modulation with ASA compared with saline and hyaluronic acid (HA) in subjects with knee OA. A total of 200 subjects were randomized 1:1:1 to ASA, HA, or saline, with subjects blinded to their allocation. Changes from baseline of patient-reported outcomes (PROs)—EQ-5D-5L, Knee Osteoarthritis Outcome Score (KOOS), visual analog scale (VAS), Tegner, and Single Assessment Numerical Evaluation (SANE)—were compared between groups. Patients reporting unacceptable pain at 3 months were considered treatment failures and withdrawn from the study. Statistical analysis was completed by comparing changes in PROs from baseline to 3 and 6 months for all groups. Comparison of demographics between treatment groups showed no significant differences between groups. Patients reporting unacceptable pain at 3 months in each group were ASA (13.2%), HA (68.8%), and saline (75%). Patients receiving ASA demonstrated significantly greater improvements from baseline for overall pain (VAS), KOOS pain, and KOOS-activities of daily living scores compared with those in the HA group (3 months) and both groups (6 months). ASA patients had significantly greater improvements in KOOS symptom scores compared with HA and saline at 3 and 6 months, respectively. OMERACT-OARSI responder rates for ASA, HA, and saline groups were 69.1, 39.1, and 42.6%, respectively (p ¼ 0.0007). Subjects receiving ASA treatment showed greater improvements in PROs and fewer patients reported unacceptable pain compared with HA and saline. The evidence presented in this Level I Randomized Controlled Trial suggests that ASA injection is an effective treatment for the nonoperative management of symptomatic knee OA.

Farr, J., Gomoll, A. H., Yanke, A. B., Strauss, E. J., & Mowry, K. C. (2019). A Randomized Controlled Single-Blind Study Demonstrating Superiority of Amniotic Suspension Allograft Injection Over Hyaluronic Acid and Saline Control for Modification of Knee Osteoarthritis Symptoms. The Journal of Knee Surgery, 32(11), 1143–1154. doi: 10.1055/s-0039-1696672

Exosomes from embryonic mesenchymal stem cells alleviate osteoarthritis through balancing synthesis and degradation of cartilage extracellular matrix

Background: Mesenchymal stem cell therapy for osteoarthritis (OA) has been widely investigated, but the mechanisms are still unclear. Exosomes that serve as carriers of genetic information have been implicated in many diseases and are known to participate in many physiological processes. Here, we investigate the therapeutic potential of exosomes from human embryonic stem cell-induced mesenchymal stem cells (ESC-MSCs) in alleviating osteoarthritis (OA). 

Methods: Exosomes were harvested from conditioned culture media of ESC-MSCs by a sequential centrifugation process. Primary mouse chondrocytes treated with interleukin 1 beta (IL-1β) were used as an in vitro model to evaluate the effects of the conditioned medium with or without exosomes and titrated doses of isolated exosomes for 48 hours, prior to immunocytochemistry or western blot analysis. Destabilization of the medial meniscus (DMM) surgery was performed on the knee joints of C57BL/6 J mice as an OA model. This was followed by intra-articular injection of either ESC-MSCs or their exosomes. Cartilage destruction and matrix degradation were evaluated with histological staining and OARSI scores at the post-surgery 8 weeks. 

Results: We found that intra-articular injection of ESC-MSCs alleviated cartilage destruction and matrix degradation in the DMM model. Further in vitro studies illustrated that this effect was exerted through ESC-MSC-derived exosomes. These exosomes maintained the chondrocyte phenotype by increasing collagen type II synthesis and decreasing ADAMTS5 expression in the presence of IL-1β. Immunocytochemistry revealed colocalization of the exosomes and collagen type II-positive chondrocytes. Subsequent intra-articular injection of exosomes derived from ESC-MSCs successfully impeded cartilage destruction in the DMM model. 

Conclusions: The exosomes from ESC-MSCs exert a beneficial therapeutic effect on OA by balancing the synthesis and degradation of chondrocyte extracellular matrix (ECM), which in turn provides a new target for OA drug and drug-delivery system development.

Wang, Y., Yu, D., Liu, Z., Zhou, F., Dai, J., Wu, B., … Liu, H. (2017). Exosomes from embryonic mesenchymal stem cells alleviate osteoarthritis through balancing synthesis and degradation of cartilage extracellular matrix. Stem Cell Research & Therapy, 8(1). doi: 10.1186/s13287-017-0632-0

Exosomes Secreted from Human-Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells Prevent Osteonecrosis of the Femoral Head by Promoting Angiogenesis

Background: Local ischemia is the main pathological performance in osteonecrosis of the femoral head (ONFH). There is currently no effective therapy to promote angiogenesis in the femoral head. Recent studies revealed that exosomes secreted by induced pluripotent stem cell-derived mesenchymal stem cells (iPS-MSC-Exos) have great therapeutic potential in ischemic tissues, but whether they could promote angiogenesis in ONFH has not been reported, and little is known regarding the underlying mechanism. 

Methods: iPS-MSC-Exos were intravenously injected to a steroid-induced rat osteonecrosis model. Samples of the femoral head were obtained 3 weeks after all the injections. The effects were assessed by measuring local angiogenesis and bone loss through histological and immunohistochemical (IHC) staining, micro-CT and three-dimensional microangiography. The effects of exosomes on endothelial cells were studied through evaluations of proliferation, migration and tube-forming analyses. The expression levels of angiogenic related PI3K/Akt signaling pathway of endothelial cells were evaluated following stimulation of iPS-MSC-Exos. The promoting effects of exosomes were re-evaluated following blockade of PI3K/Akt. 

Results: The in vivo study revealed that administration of iPS-MSC-Exos significantly prevented bone loss, and increased microvessel density in the femoral head compared with control group. We found that iPS-MSC-Exos significantly enhanced the proliferation, migration and tube-forming capacities of endothelial cells in vitro. iPS-MSC-Exos could activate PI3K/Akt signaling pathway in endothelial cells. Moreover, the promoting effects of iPS-MSC-Exos were abolished after blockade of PI3K/Akt on endothelial cells. 

Conclusions: Our findings suggest that transplantation of iPS-MSC-Exos exerts a preventative effect on ONFH by promoting local angiogenesis and preventing bone loss. The promoting effect might be attributed to activation of the PI3K/Akt signaling pathway on endothelial cells. The data provide the first evidence for the potential of iPS-MSC-Exos in treating ONFH.

Liu, X., Li, Q., Niu, X., Hu, B., Chen, S., Song, W., … Wang, Y. (2017). Exosomes Secreted from Human-Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells Prevent Osteonecrosis of the Femoral Head by Promoting Angiogenesis. International Journal of Biological Sciences, 13(2), 232–244. doi: 10.7150/ijbs.16951

Comparison of exosomes secreted by induced pluripotent stem cell-derived mesenchymal stem cells and synovial membrane-derived mesenchymal stem cells for the treatment of osteoarthritis

Background: Osteoarthritis (OA) is the most common joint disease worldwide. In the past decade, mesenchymal stem cells (MSCs) have been used widely for the treatment of OA. A potential mechanism of MSC-based therapies has been attributed to the paracrine secretion of trophic factors, in which exosomes may play a major role. In this study, we aimed to compare the effectiveness of exosomes secreted by synovial membrane MSCs (SMMSC-Exos) and exosomes secreted by induced pluripotent stem cell-derived MSCs (iMSC-Exos) on the treatment of OA. 

Methods: Induced pluripotent stem cell-derived MSCs and synovial membrane MSCs were characterized by flow cytometry. iMSC-Exos and SMMSC-Exos were isolated using an ultrafiltration method. Tunable resistive pulse sensing analysis, transmission electron microscopy, and western blots were used to identify exosomes. iMSC-Exos and SMMSC-Exos were injected intra-articularly in a mouse model of collagenase-induced OA and the efficacy of exosome injections was assessed by macroscopic, histological, and immunohistochemistry analysis. We also evaluated the effects of iMSC-Exos and SMMSC-Exos on proliferation and migration of human chondrocytes by cell-counting and scratch assays, respectively. 

Results: The majority of iMSC-Exos and SMMSC-Exos were approximately 50–150 nm in diameter and expressed CD9, CD63, and TSG101. The injection of iMSC-Exos and SMMSC-Exos both attenuated OA in the mouse OA model, but iMSC-Exos had a superior therapeutic effect compared with SMMSC-Exos. Similarly, chondrocyte migration and proliferation were stimulated by both iMSC-Exos and SMMSC-Exos, with iMSC-Exos exerting a stronger effect. 

Conclusions: The present study demonstrated that iMSC-Exos have a greater therapeutic effect on OA than SMMSC-Exos. Because autologous iMSCs are theoretically inexhaustible, iMSC-Exos may represent a novel therapeutic approach for the treatment of OA.

Zhu, Y., Wang, Y., Zhao, B., Niu, X., Hu, B., Li, Q., … Wang, Y. (2017). Comparison of exosomes secreted by induced pluripotent stem cell-derived mesenchymal stem cells and synovial membrane-derived mesenchymal stem cells for the treatment of osteoarthritis. Stem Cell Research & Therapy, 8(1). doi: 10.1186/s13287-017-0510-9

Cryopreserved amniotic membrane and umbilical cord particulate for managing pain caused by facet joint syndrome

A case series
Treatment of back pain due to facet joint syndrome has been a challenge for physicians since its recognition ∼80 years ago. Intra-articular injections of steroids, local anesthetics, and phenol have been widely adopted despite their known shortcomings. Recently,intra-articular injection of amniotic membrane-umbilical cord (AMUC) has been utilized in various orthopedic indications, including those involving synovial joints, due to its reported anti-inflammatory properties. Herein, use of AMUC for facet joint syndrome was evaluated. A single-center case series was conducted on patients presenting with pain caused by facet joint syndrome, confirmed by single blocking anesthetic injection and treated using a single intra-articular injection of 50mg particulate AMUC (CLARIX FLO) suspended
in preservative-free saline. Patient reported back pain severity (numerical scale 0–10) and opioid use were compared between baseline and 6 months following treatment.
A total of 9 patients (7 males, 2 females), average age 52.1±15.9 years, were included. Five patients with cervical pain had a history of trauma, 1 patient had suffered lumbar facet injury and 3 had degenerative lumbar facet osteoarthritis. All patients had severe pain
prior to injection (8.2±0.8) and 4 (44%) were taking opioids (>100 morphine milligram equivalents). Six-month post-treatment, average pain had decreased to 0.4±0.7 (P<.05). All patients had ceased use of prescription pain medications, including opioids. No adverse events, repeat procedures, or complications were reported. Intra-articular injection of AMUC appears to be promising for managing facet pain and mitigating opioid use. Further investigation with larger sample size is warranted.

Bennett, D. S. (2019). Cryopreserved amniotic membrane and umbilical cord particulate for managing pain caused by facet joint syndrome. Medicine, 98(10). doi: 10.1097/md.0000000000014745

Human Fetal Tissue Transplantation: Amniotic Fluid Cell Therapy to Relieve Disc-Related Low Back Pain and Its Efficacy Comparison with Long-Acting Steroid Injection

Introduction: There are many problems in case of treatment of the patients reporting with degenerated disc with or without disc prolapse, desiccation, bulge, or compression of the adjacent nerves and its implications. Most of the patients with chronic discogenic back pain, without specific history of trauma, are on geriatric age group. In this age group, low back pain is associated with varying degree of age-induced degenerative osteoporosis, spondylosis, spondyloarthrosis, intervertebral disc prolapse, or even compression collapse apart from other problems like diabetic background, hypertension, ischemic heart disease, chronic obstructive pulmonary disorder, dyslipidemia, and hypothyroidism. MRI presentation of a typical geriatric presentation of low back pain is shown (Figs. 19.1, 19.2, and 19.3).

Materials and methods: 42 patients participated and randomized in two equal groups. Group A (N = 21, male 10 and female 11, mean age 56.4 ± 8.9 year) was treated with 80 mg methylprednisolone in 10 mL water for injection under C-arm guidance in the operation theater (OT) after 1 % infiltration with Xylocaine at the site of maximum tenderness in the back. Similarly, Group B (N = 21, male 12 and female 9, mean age 59.4 ± 6.4 year) was also treated in the OT with similar protocol with 10 mL of freshly collected amniotic fluid from mothers undergoing hysterotomy and ligation. All the procedures passed through the donor and recipient’s informed consent protocol and vetted by the institute-based ethical committee.

Result and analysis: Studying and comparing the clinically manifested effect of treatment, it can be easily seen that both steroid (Group A) and cell therapy (Group B) patients showed improvement of pain and distress from the pretreatment value; however, Group B scoring is much better (p, 0.01), as seen and assessed from the value of the VAS (visual analog pain scale), WD (walking distance in meters), and HAQ (Health Assessment Questionnaire). If we see further the clinical assessment of pain relief and patient’s satisfaction as seen from Table 19.3 and Graph 19.1 in case of Group A (long-acting steroid group), it was 20/21 cases in 1st month which became 12/21 in 3rd month, 6/21 in 6th month, 4/21 in 12th month, and 2/21 after 24-month follow-up. Similarly in Group B (cell therapy patients), the identical values after the 1st month were 18/21, which became 21/21 in 3rd month, 21/21 in 6th month, 14/21 in 12th month, and 12/24 after 24-month follow-up. Another globally practiced guideline for pain assessment or scoring for comparison is Oswestry low back pain disability questionnaire. Here in Table 19.4 and Graph 19.2, we have again compared the effect of treatment of Group A (steroid) and Group B (cell therapy with fresh amniotic fluid) and followed up the results of Group A and Group B treatment as per scoring by Oswestry low back pain disability questionnaire up to 24 months. Here, postinjection with long-acting steroid (Group A) suggested a mean scoring of 9 ± 1.2 % SD after 3 months, which became mean 1.9 ± 1.2 % SD after 6 months, mean 39 ± 9.2 % SD after 9 months, mean 39 ± 8.2 % SD after 12 months, mean 41 ± 7.2 % SD after 18 months, and then ultimately mean 48 ± 12.2 % SD after 24 months. Similarly in case of cell therapy group (Group B), the mean scoring was 11.7 ± 1.6 % SD after 3rd month follow-up, which became mean 9.4 ± 0.6 % SD after 6th month, mean 9.1 ± 0.96 % SD after 9th month, mean 7.1 ± 0.6 % SD after 12th month, mean 6.7 ± 0.4 % SD after 18th month, and ultimately mean 4.1 ± 0.96 % SD after 24th month follow-up.

Discussion and conclusion: If we analyze the results, we can see long-acting steroid, due to its anti-inflammatory and other activities, causes some improvement of the patients; however, it is ill sustained as noted from the follow-up. But freshly collected simple amniotic fluid cell therapy has a much more sustained effect apart from the remarkable improvement, but the question remains why in long-term follow-up there is reappearance of pain in some of the victims』 Is it psychosomatic aspects or a recurrent cell therapy or increasing the cell dosage that can have a more sustained effect』 These are some of the questions for the future investigators in this frontline area of cellular therapy. But from an overall point of view, regeneration can only treat the root cause of degeneration of the whole lumbosacral region. Cell therapy is the only curative approach for such a generalized multisystemic deterioration of the region, and the palliative approach of pain relief with anti-inflammatory drug including steroid is short lived and has longtime use and may lead to drug-induced problems in addition of the recurrence of the symptoms.
Bhattacharya N. (2013) Amniotic Fluid Cell Therapy to Relieve Disc-Related Low Back Pain and Its Efficacy Comparison with Long-Acting Steroid Injection. In: Bhattacharya N., Stubblefield P. (eds) Human Fetal Tissue Transplantation. Springer, London

Human amniotic membrane as an alternative source of stem cells for regenerative medicine
The human amniotic membrane (HAM) is a highly abundant and readily available tissue. This amniotic tissue has considerable advantageous characteristics to be considered as an attractive material in the field of regenerative medicine. It has low immunogenicity, anti-inflammatory properties and their cells can be isolated without the sacrifice of human embryos. Since it is discarded post-partum it may be useful for regenerative medicine and cell therapy. Amniotic membranes have already been used extensively as biologic dressings in ophthalmic, abdominal and plastic surgery. HAM contains two cell types, from different embryological origins, which display some characteristic properties of stem cells. Human amnion epithelial cells (hAECs) are derived from the embryonic ectoderm, while human amnion mesenchymal stromal cells (hAMSCs) are derived from the embryonic mesoderm. Both populations have similar immunophenotype and multipotential for in vitro differentiation into the major mesodermal lineages, however they differ in cell yield. Therefore, HAM has been proposed as a good candidate to be used in cell therapy or regenerative medicine to treat damaged or diseased tissues.

Díaz-Prado, S., Muiños-López, E., Hermida-Gómez, T., Cicione, C., Rendal-Vázquez, M. E., Fuentes-Boquete, I., … Blanco, F. J. (2011). Human amniotic membrane as an alternative source of stem cells for regenerative medicine. Differentiation, 81(3), 162–171. doi: 10.1016/j.diff.2011.01.005

Exosomes derived from human embryonic mesenchymal stem cells promote osteochondral regeneration

OBJECTIVE:
Clinical and animal studies have demonstrated the efficacy of mesenchymal stem cell (MSC) therapies in cartilage repair. As the efficacy of many MSC-based therapies has been attributed to paracrine secretion, particularly extracellular vesicles/exosomes, we determine here if weekly intra-articular injections of human embryonic MSC-derived exosomes would repair and regenerate osteochondral defects in a rat model.

METHODS:
In this study, osteochondral defects were created on the trochlear grooves of both distal femurs in 12 adult rats. In each animal, one defect was treated with 100 μg exosomes and the contralateral defect treated with phosphate buffered saline (PBS). Intra-articular injections of exosomes or PBS were administered after surgery and thereafter weekly for a period of 12 weeks. Three unoperated age-matched animals served as native controls. Analyses were performed by histology, immunohistochemistry, and scoring at 6 and 12 weeks after surgery.

RESULTS:
Generally, exosome-treated defects showed enhanced gross appearance and improved histological scores than the contralateral PBS-treated defects. By 12 weeks, exosome-treated defects displayed complete restoration of cartilage and subchondral bone with characteristic features including a hyaline cartilage with good surface regularity, complete bonding to adjacent cartilage, and extracellular matrix deposition that closely resemble that of age-matched unoperated control. In contrast, there were only fibrous repair tissues found in the contralateral PBS-treated defects.

CONCLUSION:
This study demonstrates for the first time the efficacy of human embryonic MSC exosomes in cartilage repair, and the utility of MSC exosomes as a ready-to-use and ‘cell-free’ therapeutic alternative to cell-based MSC therapy.

Zhang, S., Chu, W., Lai, R., Lim, S., Hui, J., & Toh, W. (2016). Exosomes derived from human embryonic mesenchymal stem cells promote osteochondral regeneration. Osteoarthritis and Cartilage, 24(12), 2135–2140. doi: 10.1016/j.joca.2016.06.022

Mesenchymal Stem Cells for Cartilage Regeneration of TMJ Osteoarthritis
Temporomandibular joint osteoarthritis (TMJ OA) is a degenerative disease, characterized by progressive cartilage degradation, subchondral bone remodeling, synovitis, and chronic pain. Due to the limited self-healing capacity in condylar cartilage, traditional clinical treatments have limited symptom-modifying and structure-modifying effects to restore impaired cartilage as well as other TMJ tissues. In recent years, stem cell-based therapy has raised much attention as an alternative approach towards tissue repair and regeneration. Mesenchymal stem cells (MSCs), derived from the bone marrow, synovium, and even umbilical cord, play a role as seed cells for the cartilage regeneration of TMJ OA. MSCs possess multilineage differentiation potential, including chondrogenic differentiation as well as osteogenic differentiation. In addition, the trophic modulations of MSCs exert anti-inflammatory and immunomodulatory effects under aberrant conditions. Furthermore, MSCs combined with appropriate scaffolds can form cartilaginous or even osseous compartments to repair damaged tissue and impaired function of TMJ. In this review, we will briefly discuss the pathogenesis of cartilage degeneration in TMJ OA and emphasize the potential sources of MSCs and novel approaches for the cartilage regeneration of TMJ OA, particularly focusing on the MSC-based therapy and tissue engineering.

Cui, D., Li, H., Xu, X., Ye, L., Zhou, X., Zheng, L., & Zhou, Y. (2017). Mesenchymal Stem Cells for Cartilage Regeneration of TMJ Osteoarthritis. Stem Cells International, 2017, 1–11. doi: 10.1155/2017/5979741

Exosomes as potential alternatives to stem cell therapy for intervertebral disc degeneration: in-vitro study on exosomes in interaction of nucleus pulposus cells and bone marrow mesenchymal stem cells

Background: The stem cell-based therapies for intervertebral disc degeneration have been widely studied. However, the mechanisms of mesenchymal stem cells interacting with intervertebral disc cells, such as nucleus pulposus cells (NPCs), remain unknown. Exosomes as a vital paracrine mechanism in cell–cell communication have been highly focused on. The purpose of this study was to detect the role of exosomes derived from bone marrow
mesenchymal stem cells (BM-MSCs) and NPCs in their interaction with corresponding cells.

Methods: The exosomes secreted by BM-MSCs and NPCs were purified by differential centrifugation and identified by transmission electron microscope and immunoblot analysis of exosomal marker proteins. Fluorescence confocal microscopy was used to examine the uptake of exosomes by recipient cells. The effects of NPC exosomes on the migration and differentiation of BM-MSCs were determined by transwell migration assays and quantitative RT-PCR
analysis of NPC phenotypic genes. Western blot analysis was performed to examine proteins such as aggrecan, sox-9, collagen II and hif-1α in the induced BM-MSCs. Proliferation and the gene expression profile of NPCs induced by BM-MSC exosomes were measured by Cell Counting Kit-8 and qRT-PCR analysis, respectively.

Results: Both the NPCs and BM-MSCs secreted exosomes, and these exosomes underwent uptake by the corresponding cells. NPC-derived exosomes promoted BM-MSC migration and induced BM-MSC differentiation to a nucleus pulposus-like phenotype. BM-MSC-derived exosomes promoted NPC proliferation and healthier extracellular matrix production in the degenerate NPCs.

Conclusion: Our study indicates that the exosomes act as an important vehicle in information exchange between BM-MSCs and NPCs. Given a variety of functions and multiple advantages, exosomes alone or loaded with specific genes and drugs would be an appropriate option in a cell-free therapy strategy for intervertebral disc degeneration.

Lu, K., Li, H.-Y., Yang, K., Wu, J.-L., Cai, X.-W., Zhou, Y., & Li, C.-Q. (2017). Exosomes as potential alternatives to stem cell therapy for intervertebral disc degeneration: in-vitro study on exosomes in interaction of nucleus pulposus cells and bone marrow mesenchymal stem cells. Stem Cell Research & Therapy, 8(1). doi: 10.1186/s13287-017-0563-9

Human Umbilical Cord Mesenchymal Stem Cell Transplantation for the Treatment of Chronic Discogenic Low Back Pain

Background: Chronic low back pain is one of the major causes of disability and thus has a major socioeconomic impact. Intervertebral disc degeneration is the main cause of chronic low back pain. Treatment for chronic discogenic low back pain has traditionally been limited to either conservative management or surgical fusion. If conservative treatment fails, then surgical fusion is commonly considered. Current treatments are limited to treat the symptoms and not the underlying biologic alterations of the disc.

Objective: Human umbilical cord tissue-derived mesenchymal stem cells (HUC-MSCs) contain
stem cells and possess the ability to regenerate degenerative discs. Based on the results of previous in vitro and animal experiments, we conducted a preliminary study to test the feasibility and safety and to obtain an early indication for the therapeutic value of HUC-MSC transplantation in patients with chronic discogenic low back pain.

Study Design: This is the first study involving treatment of chronic low back pain using HUC- MSC transplantation.

Setting: The study was performed at a spine center in China.

Methods: Two patients with chronic discogenic low back pain were treated with HUC-MSC transplantation. An 11-point visual analog scale (VAS, 0 – 10) and Oswestry Disability Index (ODI,0 – 100) were used to assess the back pain symptoms and the lumbar function, respectively.

Results: After transplantation, the pain and function improved immediately in the 2 patients. The VAS and ODI scores decreased obviously during a 2-year follow-up period.

Limitations: The shortcoming of this study is that it is a preliminary study with only 2 patients.

Conclusion: The clinical outcomes indicated that HUC-MSC transplantation is a favorable alternative method for the treatment of chronic discogenic low back pain.

Pang, X., Yang, H., & Peng, B. (2014). Human Umbilical Cord Mesenchymal Stem Cell Transplantation for the Treatment of Chronic Discogenic Low Back Pain. Pain Physician, 17, E525–E530.

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