Objective: This study aimed to elucidate the effects of melanoma-derived exosomes on modulating the differentiation of hematopoietic stem cells (HSCs) towards immunosuppressive myeloid-derived suppressor cells (MDSCs). Materials and Methods: Exosomes were isolated via ultracentrifugation from conditioned media of the B16F10 murine melanoma cell line after adaptation to exosome-free culture conditions. HSCs were extracted from the bone marrow of adult C57BL/6 mice through density gradient separation and MACS column isolation of CD133+ and CD34+ populations. HSCs were cultured with or without B16F10 exosomes for 24 hours. Flow cytometry analyzed the expression of canonical MDSC surface markers CD11b, Ly6G, and Ly6C. Levels of the immunosuppressive cytokines interleukin-10 (IL-10) and tumor necrosis factor beta (TGF-β) in HSC culture supernatants were quantified by ELISA. Results: Compared to untreated controls, HSCs treated with B16F10 exosomes displayed significantly increased percentages of CD11b+Ly6G+ granulocytic MDSCs and CD11b+Ly6C+ monocytic MDSCs, with a notable predominance of the Ly6G+ granulocytic subtype. Additionally, exosome-treated HSCs secreted markedly higher levels of the cytokines IL-10 and TGF-β, which are involved in MDSC-mediated immunosuppression. Conclusions: Our findings demonstrate that melanoma-derived exosomes can orchestrate the differentiation of HSCs into MDSCs with an immunosuppressive phenotype, as evidenced by the upregulation of MDSC surface markers and secreted cytokines. This supports a role for tumor-derived exosomes in driving the systemic expansion and accumulation of immunosuppressive MDSCs through the reprogramming of HSC fate. Elucidating the exosome contents and HSC signaling pathways involved could reveal therapeutic strategies to block this pathway and enhance anti-tumor immunity.
The skin is the largest organ in the human body and plays a significant role in protecting the body from external threats, containing tissues that sustain the body's homeostasis. Wound healing in the skin is a complex process involving the interaction of various cell types in the target tissue, including but not limited to cytokines and growth factors. In extreme cases, disorders of the cardiorespiratory system, such as chronic diseases, may prevent the process of wound healing entirely. Numerous studies have been conducted to discover methods to restore the ability of chronic wounds to cure themselves, but this remains one of the most significant medical problems. Exosomes derived from stem cells have been extensively proposed as a treatment for dermal wound recovery. Different types of stem cells have varying therapeutic potential. Exosomes, a component of paracrine, have the function of enhancing the effectiveness of stem cells. This article discusses the wound healing process as well as the mechanism of stem cell and adipose-derived exosome therapy on cutaneous wound healing and its clinical applications.
Colorectal cancer (CRC) treatment using common chemotherapy approaches has drawbacks such as side effects, costs, and resistance of cancer cells which affects patients’ prolonged survival, and quality of life. The immune cells have pivotal roles in regulating tumor progression in the tumor microenvironment (TME). The most important CRC cellular immunotherapies include the use of tumor-derived cells such as tumor-infiltrating lymphocytes (TILs) and lymph node lymphocytes (LNLs), peripheral blood mononuclear cells (PBMCs), derived cells, including T cells, natural killer (NK) cells, cytokine-induced killer (CIK) cells, and chimeric antigen receptor (CAR) cells. Although adoptive cell therapy has some advantages, some disadvantages have been reported. TILs cells are strictly directed against tumor-specific antigens; however, they are inefficient due to immune editing. CIK cells have a major histocompatibility complex (MHC)-independent cytotoxic effect and need concurrent high-dose interleukin (IL)-2 administration. In addition, chimeric antigen receptor-T cells (CAR-T cells) are MHC-independent that overcome MHC downregulation by the tumor. They are potent in recognizing any cell surface antigen and are applicable to a broad range of patients and T-cell populations. Here, the researchers present the most popular cancer cellular immunotherapy approaches and discuss their clinical relevance by referring to data obtained from CRC clinical trials. To date, clinical experience and efficacy suggest that combining more than one immunotherapy intervention, in combination with other treatments like chemotherapy, radiotherapy, and targeted therapy, is promising for cancer therapy.
BACKGROUND: The aim of this case study was to investigate the safety and efficacy of the SONG Laser Protocol in the context of dementia. Our hypothesis is that the SONG Laser Protocol, when administered intravenously, may have a beneficial effect on the alpha waves [as assessed by electroencephalography (EEG)] in a patient suffering from dementia. CASE REPORT: This was a case study focusing on a single patient suffering from dementia. The SONG Laser Protocol was delivered in a clinical setting, and the primary outcome measures were the amplitude of alpha waves as seen in EEG, the target frequency of the alpha waves, and the power spectrum density. The pre- and post-SONG Laser Protocol EEGs were compared. A clear increase in alpha wave activity on Day 3 post-SONG Laser Protocol was detected. The alpha wave target frequency increased to 8.0 (normal range 8.0-12.0), and the power spectrum density (PSD) increased by 65%. The patient also expressed feelings of improved well-being following the SONG Laser Protocol. CONCLUSIONS: The SONG Laser Protocol may have a beneficial effect on alpha wave activity in a patient suffering from dementia. Clinical trials are needed to confirm safety and efficacy.
Modeling the human brain in order to study its physiology, development and diseases has been very challenging due to its structural and functional complexity and fragility. Brain organoids, derived from human pluripotent stem cells, opened a new approach to create in vitro 3D models, that more closely resemble the complexity of the brain, as compared to 2D cell cultures. So far, multiple developmental and neurodegenerative diseases have been generated with organoid technology and used as drug screening platforms not only to accelerate the development of more efficient treatments but also to get one step closer to personalized medicine. This review aims to showcase the current applications of brain organoids and review future perspectives and limitations.
Cardiovascular diseases are among the major causes of death worldwide. These diseases can be described as circumstances in which cell loss and injury exceed the capacity for regeneration and repair. Many therapeutic approaches have been developed to prevent and cure these diseases. Because the adult mammalian heart has limited regenerative capacity, harnessing the power of stem and progenitor cells could be one of the most promising approaches to regenerate and repair injured cardiac and vascular tissue. The natriuretic peptide system plays a key role in orchestrating the mammalian heart development. Studies have reported that the natriuretic peptide system has been implicated in the proliferation and differentiation of cardiomyocytes derived from embryonic stem cells, cardiac progenitor/stem cells, and mesenchymal stem cells. Besides, after cardiac damage and ischemic events, the revascularization of the ischemic areas improves cardiac function and delays the onset of heart failure in myocardial ischemia patients. Studies have shown that the natriuretic peptide system can promote vascular regeneration and repair, resulting in improved heart function after an ischemic event. Combining the exogenous administration of natriuretic peptide with stem/progenitor cells differentiating into cardiovascular system cells could be one of the most effective therapies for replenishing and replacing lost or injured cardiac and vascular tissue and cells. As a result, the natriuretic peptide system may play a role in cardiovascular protective and regenerative processes, as well as the proliferation and differentiation of relevant stem cells into cardiomyocytes, endothelial cells, and smooth muscle cells, via their receptors. In this review, we provide an overview of cardiovascular regenerative medicine and examine the potential applications of the natriuretic peptide system in cardiovascular repair and regeneration.
This short review explores the constantly evolv- ing technology, both cellular and equipment or technology based, which is currently being ex- perienced in the field of regenerative medicine. There is considerable ongoing research into stem cell technologies but there is currently a translational block in bringing some of these technologies to the clinic. We propose new and evolving technologies which may resolve this cell-based block and quickly bring regenerative medicine technologies safely and effectively to patients in need
My dear friend, colleague and mentor Bob Edwards (who received the Nobel Prize for his work on in vitro fertilisation) (IVF) actually had a deep and profound interest in stem cell technology1-3. I was even lucky enough to be supervised by Bob Edwards for my PhD at Cambridge University on the stem cells found in the developing mouse embryo. IVF and stem cell technology, therefore, have a long history together which few people may realise. Despite this long joint history there has been little progress in the use of stem cell technology in IVF. This Editorial will briefly explore the past history of stem cells in IVF and then look at the future which is not only potentially exciting but also potentially ground-breaking. Perhaps the most obvious link to IVF and stem cells is the development of human embryonic stem cells (hESC) from the inner cell mass of human embryos4. Whilst hESC are pluripotent and, therefore, an excellent candidate for gamete production, very little progress has been made because of the legal, ethical, moral and religious objections to creating hESC which requires the destruction of a viable human embryo5. More recently, it has been shown that mouse pluripotent mouse ESC can be reprogrammed into totipotent cells6 which have been termed totipotent-like stem cells (TLSCs). It is possible that these TLSCs may give new insights into totipotency and embryology. Induced Pluripotent Stem Cells (iPSCs) have a similar history when it comes to IVF. These are somatic cells (e.g. skin cells) which are ‘transformed’ into pluripotent stem cells by the introduction of various genes7. These iPSCs are pluripotent and autologous so they have the ability, in theory, to carry out gametogenesis8 in patients undergoing fertility treatment. The problems with the routine clinical use of iPSCs in fertility treatment is the cost but most importantly ongoing safety concerns about iPSCs because of the genes needed to be inserted to convert a somatic cell into a stem cell9. Mesenchymal stem cells (MSCs) can be obtained from adipose tissue, bone marrow, the umbilical cord and even inside teeth10. These MSCs can produce bone, connective tissue and adipose tissue and there are some data suggesting that MSCs may be useful in premature ovarian failure11. The drawbacks of using MSCs in the treatment of infertility are the cost and the standardisation of MSCs to ensure safety and efficacy12. All of these stem cell types have their problems when considering their use in the treatment of infertility. It may be many years, if ever, before they come to routine clinical practice in the treatment of infertility. It has been shown that human Very Small Embryonic-Like (hVSEL) stem cells are found in every tissue of the body and in the peripheral blood13. They can easily be obtained from peripheral blood by preparing Platelet Rich Plasma (PRP) which has high numbers of hVSEL stem cells14. The hVSEL stem cells are pluripotent and arise from the primordial germ cell15 making them the ideal stem cell to use in autologous format in the treatment of infertility16. Most workers agree that the hVSEL stem cells in the peripheral circulation are biologically inactive (quiescent)17. Despite this, we have shown that hVSEL stem cells in PRP made from peripheral blood can be biologically activated by a modulated laser (called the QiLaser). Following exposure of the QiLaser to hVSEL stem cells in PRP they become biologically active possibly through a mechanism of action involving quantum mechanics14,18. This means that in hVSEL stem cells we have a source of biologically active pluripotent stem cells which can be easily collected from peripheral blood for autologous treatment14. This makes hVSEL stem cells an ideal candidate stem cell to treat both male and female infertility very easily and cheaply19. Further clinical trials are needed in order to fully assess the potential of autologous QiLaser activated hVSEL stem cells in PRP. Our unpublished data to date show significant benefits of simple intravenous infusion of QiLaser activated hVSEL stem cells not only in the treatment of infertility but also in the treatment of the menopause. These QiLaser activated hVSEL stem cell technologies hold great hope for a new generation of treatments for infertility, which may revolutionise the way in which we think about and treat this condition.
Objective: The peculiarity of immune response during and after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is of special interest as this may contribute to the development of an efficient diagnostic approach. Data characterizing humoral or T-cell mediated immune responses after SARS-CoV-2 infection are available, although the same sample determination of both these biomarkers of immune response has not been performed yet. Materials and Methods: We have determined the biomarkers related to humoral and T-cell-mediated immune response after SARS-CoV-2 infection by using the enzyme-linked immunosorbent assay (ELISA) method in blood samples of 49 patients who recovered from COVID-19 (35 females and 14 males; age range: 17-55 years) after paucisymptomatic disease that did not require hospitalization nor corticosteroid therapy. In all participants, SARS-CoV-2 infection was documented through clinical symptoms and polymerase chain reaction (PCR) test for SARS-CoV-2 performed through a nasopharyngeal swab. Results: It has been revealed that: a) 28 (57.1%) participants were positive for biomarker of humoral immune response against SARS-CoV-2, and b) negative (16 cases; 32.7%) or equivocal (5 cases; 10.2%) for biomarker of humoral immune response against SARS-CoV-2. Patients with a negative status of immunoglobulin G (IgG) antibodies directed against SARS-CoV-2 nucleocapsid protein exhibited an increased expression of specific biomarkers of T-cell-mediated immune response (Ki67 and IL-2). Conclusions: SARS-CoV-2 infection can induce both a humoral and a T-cell-mediated immune response. Yet, the regulatory mechanisms of this process should be further investigated. Future and larger case-control studies with additional biomarkers of SARS-CoV-2-specific immune response are warranted to confirm our preliminary findings.
In this review we explore the clinical importance of human Very Small Embryonic Like (hVSEL) stem cells as a source of pluripotent stem cells for use in regenerative medicine procedures. Autologous pluripotent hVSEL stem cells are a valuable resource in regenerative medicine especially when activated with Strachan-Ovokiatys Node Generator (SONG) modulated laser light. The review provides an overview of hVSEL stem cell technology and some insights into the massive potential of SONG modulated laser activated hVSEL stem cells regenerative medicine.
Objective: The unique mechanisms of immune regulation in the liver allow it to provide local and systemic immune tolerance to own and foreign antigens as a homeostatic condition via different T cell subsets and after liver transplantation (LT) while preserving an effective immune response against pathogens. Therefore, we aimed to analyze the Th17 and Treg subsets in the post-transplant period in patients with LT on immunosuppressive therapy and Treg/Th17 cell ratio and soluble CD30 (sCD30) as possible additional markers for characterizing the immune status of transplanted patients. Patients and Methods: The study group consisted of 17 patients after LT on immunosuppressive therapy and 10 healthy controls. We assessed Th17 (CD3+CD4+CD183–CD194+CD196+CCR10–), Treg cells (CD3+CD4+CD25+CD127-/low and CD4+CD25+ Foxp3+), Treg/Th17 ratio in peripheral blood by flow cytometry, and soluble CD30 (sCD30) in serum by ELISA. Results: The mean percentage of T regs (mean ± SD% of CD4+cells) were 5.26±2.21 and 5.17±2.12, assessed by peripheral and cytoplasmic staining, respectively (p<0.0001, r=0.9588). LT patients showed significantly higher percentages of Th17 in peripheral blood than healthy controls (7.23% vs. 3.55%, resp.) and reduction in Treg - 5.26% vs. 7.82%, resp. (p<0.05). Treg/Th17 ratio in healthy controls averaged 2.31, while in the LT group, it was significantly lower - 0.73 (p<0.05). We also observed significantly higher sCD30 levels in patients 45.47±23.62 ng/ml compared to the healthy controls 15.63 ±5.69 ng/ml (p<0.05). No significant associations were found between the CD4+ subsets with serum CD30 levels were demonstrated. Conclusions: This pilot study showed both reduced immune tolerance and increased activation of the immune system in LT patients compared to healthy controls. However, additional studies are needed to confirm and expand these results because the immune balance in our transplanted patients is a complex interaction between a tolerogenic liver, an immune response against liver graft and immunosuppressive therapy.
TLR4 is a transmembrane receptor of the innate immune system that recognize LPS of gram-negative bacteria. Its stimulation induces pro-inflammatory responses and also modulates adaptive immunity. In this article, we discuss the role of TLR4 in the activation and proliferation of T cells at the onset of autoimmune diabetes. We review the pathways involved in these observations. Finally, we show how targeting TLR4, by a variety of strategies, can prevent the occurrence of the disease but also its recurrence after allogeneic islet of Langerhans transplantation.
OBJECTIVE: Human umbilical cord Wharton’s Jelly derived MSCs (WJ-MSCs) are reported as the most potent cell source of mesenchymal stem cells, however they remain understudied in comparison to autologous sources. This study aimed to evaluate the safety of WJ-MSC therapy for a range of conditions and administration routines, including intravenous, intrathecal, and intraarticular delivery. PATIENTS AND METHODS: 22 subjects were retrospectively evaluated for adverse events following treatment with 1x108 WJ-MSCs for a range of conditions including neurological and osteoarthritic indications. Subjects were treated at Blue Horizon International (BHI) clinical sites; 13 subjects at BHI Slovakia (Nemocnica Malacky hospital, Slovakia) and 9 subjects were treated at BHI Jamaica (Montego Bay St. James and Ochos Rios, Jamaica) between 2018 to 2021. Subjects received 1 – 3 dosages of WJ-MSC via intravenous, intrathecal, or intraarticular administration depending on the indication. RESULTS: Subjects were followed on for 6-months and the incidence of adverse events recorded. In total this study reported AEs in 3 subjects from the 32 doses administered in this study, resulting in an AE rate of 9.3%. Reported AEs consisted of chills and headaches both transient and mild, and resolved without concern. Blood profiling of 75 markers for health and disease in a single subject reported that WJ-MSC treatment poses no hematological safety concern, with only one dietary related marker showing marked change during the follow up period. In contrast, several out of reference hematological markers were corrected 8-months after WJ-MSC therapy. CONCLUSIONS: We highlight the minimal occurrence of adverse reactions, most commonly chills and headache associated with intrathecal administration, following WJ-MSC therapy. Overall, this study supports the use of WJ-MSC therapy for various indications and provides safety data for future prospective studies.
In this opinion paper, we discuss the implementation of Th17 cells in the pathophysiology of SARS-CoV-2 infection, with regard to cytokine storm, acute respiratory distress syndrome (ARDS), and other COVID-19 complications. Indeed, the imbalance of IL-17 cells and the consequent inflammatory process are key players in the persistent immune activation and development of cytokine storm. We also discuss the different treatment modalities for targeting the Th17 pathway, which may be helpful in managing severe COVID-19 patients with a prominent Th17 profile.
This review examines the current status of various cellular and non-cellular regeneration technologies used for the repair and regeneration of damaged connective tissue. The article explores the clinical use of bone marrow-derived mesenchymal stem cells, adipose tissue-derived mesenchymal stem cells, growth factors, cytokines, platelet-rich plasma and GOLDIC® method. To compare the regenerative capacity of these technologies, a systematic analysis of the regeneration quality is necessary, and a high-resolution magnetic resonance imaging (MRI) using a quality scoring system is needed. It is likely that in future clinical practice a combination of such technologies will offer the optimal treatment to patients with different connective tissue disorders, which must always be our ultimate goal.
This opinion paper examines the current status of cord blood stem cell technology using volume reduction and describes a novel cord blood collection, processing and storage system. This technology could represent a new paradigm in using cord blood in regenerative medicine in the future. The decline in the use of cord blood to treat blood disorders, largely driven by haploidentical transplantation, may in the future be replaced by using cord blood in regenerative medicine procedures. The Evo3medica Sterile Closed Cryo-System (ESCCS) provides a closed cord blood collection, processing and storage system which will considerably reduce the cost of cord blood collection, processing and storage. The ESCCS enables easy collection, processing and storage of whole cord blood, with all of its constituent cells available for future regenerative medicine procedures. This will enable current cord blood banks to easily and cost-effectively switch their focus to regenerative medicine procedures. This is instead of focusing on the ever-decreasing use of cord blood in haemopoietic stem cell transplantation for blood disorders.
This opinion paper reviews the use of expanded bone marrow mesenchymal stem cells (MSCs) in the treatment of musculoskeletal diseases, especially osteoarthritis and traumatic joint damage. This paper assesses past and present stem cell-based technologies, possible concerns about safety and efficacy, alternative or possibly parallel therapies using platelet rich plasma (PRP) and exosomes, as well as the latest concepts in modulated laser activation of stem cells. The clinical trial status and medical literature on this subject are considered, and the latest Good Manufacturing Practice (GMP) bioreactor technology is proposed as the gold standard for MSC expansion.
Objective: Peripheral arterial disease (PAD) is a chronic arterial occlusive disease which mostly affects the arteries of the lower extremities. PAD morbidity generally ranges from 3% to 10%, although it increases with advancing age and can be greater than 15% in subjects over 60 years of age. In small trials, autologous bone marrow aspirate stem cell concentrate (BMAC) has proven to be safe and effective in promoting angiogenesis in patients with PAD. In this small pilot, open-label, non-randomized, noncontrolled study, we assessed the safety and feasibility of periarterial BMAC injection and implantation for treatment of patients with PAD who are not susceptible to conventional endovascular or open revascularization. Patients and Methods: A total of 27 patients with non-revascularizable CLI (Fontaine stages III and IV) were enrolled between 2015 and 2019. Comorbidities and risk factors for PAD such as diabetes, hypertension, dyslipidemia and cigarette smoking were also evaluated. Results: A total of 27 patients (M/F: 25/2) with non-revascularizable critical limb ischemia (stages III and IV according to Fontaine classification) were enrolled between 2015 and 2019. Comorbidities and risk factors for PAD such as type 2 diabetes, hypertension, cigarette smoking and dyslipidemia were also evaluated. The prevalence of cigarette smoking was high (74%; 20 patients). During the follow-up, only 4 patients underwent amputation of the limb affected by critical ischemia. In such subgroup, all patients had a Fontaine stage IV PAD. The remaining 23 patients showed a remarkable improvement in clinical features and ankle-brachial index (ABI) values, without undergoing lower-limb amputation. Computed tomography angiography (CTA) performed 3 months after the periarterial BMAC injection confirmed the presence of neovascularization in 24 out of 27 patients. The procedure was well-tolerated by all patients. Conclusions: Our study showed that periarterial BMAC injection is a safe and feasible approach for obtaining clinical improvement and short-term induction of neovascularization in patients with severe PAD.
Objective: The conventional method of harvesting the Stromal Vascular Fraction (SVF) from adipose tissue is enzymatic digestion of extracellular matrix (ECM) from the lipoaspirate. This process necessarily affects the viability and potency of the cells, eliminates the majority of pericytes embedded in the fibrous matrix and structural/functional support of ECM. Patients and Methods: Thirteen healthy subjects underwent abdominal liposuction and the aspirates were split into enzyme and mechanical digestion of stromal vascular fraction (E-SVF and M-SVF, respectively). The E-SVF and M-SVF were mixed with the ECM concentrate (buffy coat) to form the “Stromal Vascular Matrix” (SVM). The SVM was then compared to E-SVF and M-SVF. Results: The preparation of SVM using the LipocubeTM mechanical digestion technology results in a source of autologous and minimally manipulated adipose-derived stem cells for use in cosmetic and regenerative medicine procedures. Cell counts, viability assessments, CD antigen expression and gene expression analysis showed that the SVM is an optimal product for therapy. Conclusions: The SVM has a higher regenerative cell potency and provides a greater ECM support compared to common enzymatic digestion methods. In clinical applications, SVM seems to be suitable for suboptimal recipient conditions and skin regeneration purposes.
In this review we explore the past, present and future treatment of osteoarthritis using autologous and allogeneic bone marrow mesenchymal stem cells (MSCs). Osteoarthritis is one of the most prevalent joint diseases worldwide. It causes pain, loss of function and may lead to disability. At a cellular level, osteoarthritis causes biochemical changes in the composition of cartilage leading to progressive tissue degeneration. The majority of conventional treatments involve symptom control but offer only modest clinical benefits without any reversal of the cellular degeneration. Cell-based therapies in animal models have shown encouraging results and there are now a number of human case reports, pilot studies and follow-up studies that demonstrate the reversal of lesion formation. Opus Biological has designed a therapy and follow-up algorithm utilizing the feasibility and safety studies conducted in recent years to offer patients MSCs as a valid alternative to other conventional therapies for treatment of chronic osteoarthritis. MSC therapy for osteoarthritis does not require hospitalization, is a minimally invasive and low risk procedure, provides pain relief and significantly improves cartilage quality thereby enhancing joint function. IntroductIon Osteoarthritis (OA) is the most prevalent chronic joint disease as well as a frequent cause of joint pain, functional loss and disability1,2. The disease most commonly affects the joints of the knees3, hands4, feet5 and spine6. It is also relatively common in shoulder7 and hip joints8. Even though OA is most commonly related to aging9, there are also a number of modifiable and non-modifiable risk factors for the development of this condition. These include obesity10, lack of exercise11, genetic predisposition12, bone mineral density status13, occupational injury14, trauma15 and female sex (due to menopause)16. Globally there is an estimated 10-15% prevalence of OA, with the numbers higher in the female population17. OA is an increasing risk to our global community due to the advances in medicine leading to an aging population and due to increases in the prevalence of modifiable risk factors such as obesity18. According to recent estimates, by 2050 the number of people aged over 60 will account for more than 20% of the world’s population. By 2050, 130 million people will suffer from OA worldwide, and 40 million will be severely disabled by the disease. A World Health Organization report estimates that of 20% of those aged over 60, a conservative 15% will have symptomatic OA, and 33% of these people will be severely disabled by OA19. The cost to society of OA can be measured not only in the cost of adaptive aids and devices but also in the cost of medication, surgery20, nursing care, residential care, and time off work and subsequent social care relating to sick This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License Category: Review 2 P. Hollands, D. Porter Treatment of Osteoarthritis with Autologous and Allogeneic Expanded Bone Marrow Mesenchymal Stem Cells were initially termed “colony-forming unit fibroblasts” (CFU-Fs)46. Clinical trials investigating the use of MSCs began in 1995, with the results demonstrating no adverse reaction and no safety concerns, and since then hundreds of clinical trials have followed47. In 2006, The International Society for Cellular Therapy (ISCT) published the criteria for defining MSCs48. The ISCT stated that MSCs must be plastic-adherent under standard in vitro culture conditions; express CD105, CD73, and CD90, and lack expression of CD45, CD34, CD14 or CD11b, CD79a, CD19, and HLA-DR (as assessed by flow cytometry). In addition, the ISCT stated that MSCs must be able to differentiate into osteoblasts, adipocytes and chondrocytes in vitro48. MSCs have been shown to be present in bone marrow49, umbilical cord blood (with an associated clinical trial to treat cerebral palsy)50, umbilical cord tissue51, placenta52, amniotic membrane53, amniotic fluid54, periosteum55, trabecular bone56, adipose tissue57, synovium58, skeletal muscle59 and deciduous and permanent teeth60. Independent of their origin, MSCs are capable of differentiating in vitro into different cell types of the connective tissue lineages such as bone, fat, muscle, tendon and ligament as well as cartilage61. MSCs have been shown to elicit immunosuppressive and immunomodulatory effects62 on T lymphocytes63, B cells64, dendritic cells (DCs)65 and natural killer (NK) cells66. These effects occur either via the cell-cell interaction route67 or via the secretion of anti-inflammatory molecules such as indoleamine 2,3-dioxygenase (IDO)68, prostaglandin E2 (PGE2)69, interleukin-4 (IL-4)70, interleukin-10 (IL-10)71 and transforming growth factor beta (TGF-b)72. These properties make MSCs the ideal choice for cell-based regenerative medicine procedures73. The ability to differentiate in vitro into chondrocytes74, combined with their anti-inflammatory and immunomodulatory properties, make MSCs the obvious choice for the treatment of diseases such as OA75. Autologous76 or allogeneic77 bone marrow-derived MSCs are the most widely used MSCs in clinical research and treatment modalities across a plethora of disease indications, and are often considered to be the gold standard MSC type78 because of the characterization that has occurred exhaustively over the last 5 decades79. Over the last 25 years the surgical implantation of autologous chondrocytes has been used to treat pay. International institutions have been reluctant to put a figure to the large indirect costs derived from the decrease in productivity caused by OA.
