Background and clinical application of MSCs in regenerative medicine
Globally, in the last decade, there has been considerable interest and experience gained in the use of mesenchymal stem cells (MSCs) for cell-based therapies.
MSCs are playing a significant role in the field of regenerative medicine and have featured in clinical trials focussing on the treatment of a range of disorders including but not limited to musculoskeletal, neuronal, cardiac, hepatic, ocular, cutaneous and GI tract conditions. Additionally, their potent immunotherapeutic effects have been harnessed in the treatment of diabetes, respiratory disease including Covid 19 complications and modifying certain side effects of stem cell transplantation for blood and bone marrow diseases (1-6). This mini review sets out to discuss the therapeutic potential of MSCs across a range of applications, address how they function clinically and touch on future possibilities.
How do MSCs help clinically?
The therapeutic potential of MSCs is attributed to complex cellular and molecular mechanisms which are gradually being unravelled by intensive clinical and research studies. MSCs may under certain conditions develop into other cell types in vitro (in the laboratory) and in vivo (in the body), however, it has now been recognised that they have other valuable properties. Importantly, they are able to reduce overactive immune responses, they possess anti-inflammatory properties and can also secrete a range of proteins that facilitate tissue repair at the site of injury (7-9).
Different sources of MSCs – do they vary?
MSCs can be derived from a broad range of sources including adipose tissue, bone marrow, umbilical cord tissue and umbilical cord blood and this can influence the properties that they possess as not all MSCs are identical. Bone marrow derived MSCs for example, are particularly useful for tissue engineering, often used in conjunction with bio- inert scaffolds, as they have superior capacity for bone and cartilage formation (10). On the other hand, umbilical cord tissue derived MSCs exhibit biological advantages relative to other adult sources, including their capability to grow for longer in cell culture and this allows for larger-scale expansion without differentiation into unwanted cell types. They have also been shown to possess enhanced anti-inflammatory and immunomodulatory effects (11-12).
Taking MSC based therapies from bench to bedside: the importance of clinical trials
Registered clinical trials, have included Phase I to phase IV investigations. Phase I trials focus on determining the safety of a novel treatment while later trials look at the effectiveness of dosage, dose frequency, treatment intervals and method of delivery.
Many clinical studies utilising MSCs have been reported as confirming the safety profile of treatment strategies. Nonetheless there have been some perceived risks associated with MSC based therapeutics relating predominantly to tumorigenicity (cancerous growth), a tendency to cause inflammation and fibrosis (scarring) and thromboembolism (clotting). Fortunately, major adverse events have proven to be rare according to clinical trial evaluations, however further larger controlled clinical trials with longer follow up of patients are still required to fully determine the full safety profile of MSCs used as a cellular product (13-14).
As of April 2023, there had been 1120 registered clinical trials using MSC therapies worldwide and 12 MSC therapies that have been approved by regulatory authorities. The latter category includes MSC treatments for clinical conditions including but not limited to perianal fistula in Crohn’s disease, critical limb ischemia, spinal cord injury, osteo-arthritis, eye damage, complications of bone marrow transplantation and amyotrophic lateral sclerosis (ALS), a neurological disorder that affects the nerve cells in the brain and spinal cord that control muscle movement and breathing (15).
MSCs in regenerative medicine
In the field of regenerative medicine, which is an exciting area of clinical activity, the aim is to help repair tissues and organs that are damaged in some way. MSCs possess the remarkable ability to migrate towards sites of tissue damage by travelling through the blood stream following complex cell signalling pathways. Once recruited to the injured site, MSCs contribute to repair and regeneration through activation of several biological mechanisms including the secretion of potent molecules. Several studies indicate that MSCs only remain at the site of injury transiently and then disappear. This suggests that they are helping to activate the body’s own repair mechanisms via cross-talk between the MSCs and the damaged tissue environment. An interesting example of regenerative medicine in action is the treatment of cardiac disease, where MSCs have been utilised in a limited number of clinical trials. It has been suggested that MSCs can potentially protect the myocardium (heart muscle) by reducing the level of inflammation, promoting the differentiation of myocardial cells around areas damaged by heart disease, increasing resistance to heart muscle death, inhibiting fibrosis (scarring), and promoting new blood vessel formation which are all ideal qualities for cardiovascular repair (16-18).
MSCs and their potential in reducing transplant related complications
Haematological Transplantation
In addition to regenerative applications, MSCs have recently been investigated for their potential to support patient recovery following bone marrow transplantation for malignant or non-malignant haematological (blood and bone marrow) diseases. When donor bone marrow stem cells are infused into a patient (in a bone marrow transplant for example), the healthy donor immune cells can mount an attack on any of the tissues and cells in the recipient in a process called Graft vs Host Disease (GvHD). This reaction is desirable when the cells being destroyed are the malignant or diseased cells in the patient, but unfortunately normal cells may also be attacked which can be potentially serious. By including an infusion of MSCs in association with the donor stem cells the immunological attack can be suppressed to help reduce the severity of GvHD symptoms. Although this intervention is considered safe, more studies are required to establish the full potential of MSC therapy in protecting patients against the adverse effects of GvHD (19).
Organ transplantation
Organ transplantation is essential for saving and enhancing the lives of individuals suffering from end-stage organ failure and some of the properties of MSCs, particularly their immunomodulatory potential, make them possible candidates for use in this setting. Early work has exploited this approach in patients receiving liver or kidney transplantation where postoperative immune rejection can be a serious and fatal complication. Patients typically take immunosuppressive drugs for a long time or even for their entire lives after transplant. These drugs can cause a range of side effects which can be difficult to manage. MSC-based therapy has been shown to allow a reduction in the use immunosuppressive drugs in some cases, however, as with all early-stage therapeutic innovations, large- scale and longer-term clinical trials are required to determine the clinical potential of this intervention (20-22)
Molecules secreted by MSCs are critical to their therapeutic potential
It has been recognised for quite some time that the main mode of action on the part of MSCs, does not come from direct cellular replacement of diseased or damaged tissues. In response to their surrounding environment, MSCs secrete a broad range of bioactive molecules collectively known as “the secretome”. The MSC secretome can influence neighbouring cells and regulate multiple biological processes. The secreted factors are responsible for the anti- inflammatory, immunomodulatory and tissue healing properties of MSCs (23-25).
In the context of secreted factors, there is increasing focus on the therapeutic potential of MSC derived extracellular vesicles (MSC-EVs) which are one particularly useful component of the secrotome. Extracellular vesicles are a diverse collection of very small spherical membrane enclosed capsules, containing a biologically active cargo of important proteins including growth factors, signalling and adhesion molecules, antigens and enzymes, lipids and nucleic acids which are deliverable to target cells. The underlying mechanisms attributed to the therapeutic action of MSC-EVs relies on the transfer of their biologically active payload to damaged tissues where they can exert a beneficial effect.
In the field of regenerative medicine one area of keen interest is the treatment neurological conditions such as Parkinson’s disease. It has been shown that following intravenous infusion of MSCs, the cells cannot efficiently cross the blood–brain barrier which means that in they may not readily travel to the site of tissue injury within the brain. Applying novel MSC delivery methods such as via intra-lesion (directly into the damaged area), intra-nasal (via the nose), or spinal canal routes may solve this problem in part, however the exploitation of secreted factors rather than utilising the whole cells, has emerged as a potential solution (26-27).
Following clinical trials, efforts are moving gradually to developing MSC-EVs as a realistic therapeutic option in neurological and other disorders. However, critical issues being investigated include determining optimal sources of MSCs to yield EVs along with their production, dosages and routes of administration. Addressing these challenges will potentially lead to appropriately powered clinical trials and thus expand the therapeutic potential of MSC-EVs (28).
Using MSCs or their products which have been extracted from various source tissues
In all cases, prior to clinical application, any extracted MSCs used in a cellular therapy, or their secreted products, must be processed from bench to bedside according to Good Manufacturing Practice (GMP). This ensures the extraction and expansion of carefully controlled Advanced Therapy Medicinal Products (ATMPs) according to stringent regulated conditions.
Pharma or specialist laboratories produce ATMP grade MSC products which are typically derived from altruistically donated tissues such as cord tissue. The original tissues or cells are processed to yield MSCs which are then cultured ex vivo (in a laboratory) to yield expanded cell numbers for therapeutic application.
The FamiCord group are an active player in this field with certain of their laboratories generating ATMP products for therapeutic use (29). As of May 2024, FamiCord’s laboratories have issued cord blood or tissue derived ATMP products for the treatment of over 1,800 patients with these innovative therapies.
Harnessing the potency of MSCs present in cord blood to treat cerebral palsy and autism
As far as cell based treatments are concerned, this review has concentrated on discussing the status of MSCs used as a homogeneous (uniform) cellular product following extraction and expansion ex vivo. However, some regenerative applications use standard, processed cord blood thus harnessing the power of the MSCs contained therein, without isolating them.
An excellent example of this is the use of autologous (self to self) or sibling cord blood to treat children with cerebral palsy. The haematopoietic stem cells within these cord blood infusions, which can give rise to blood and immune cells, are unlikely to play a part in addressing the cerebral palsy symptoms. It is now recognized that it is the MSC fraction within the cord blood that plays a key role in generating the therapeutic effect. There is encouraging data from global trials, indicating that cord blood which has not been subjected to any extra processing to extract MSCs, is beneficial in improving motor function after brain injuries, including cerebral palsy.
It is thought that MSCs may be acting in the damaged brain through cell to cell signalling to promote mechanisms that reduce inflammation, inhibit neuronal cell death and stimulate angiogenesis (blood vessel formation) and/or synaptogenesis (new nerve fibre connections). The MSCs within cord blood also seem to enhance migration and proliferation of existing neural stem cells within the brain to prevent and/or repair injury thereby supporting repair at the site of injury (30-31). Interest has also grown concerning the use of cellular therapies for autism spectrum disorder (ASD) with MSCs being implicated as key effector cells although mechanisms of action have not been determined (32-33). In phase I and II clinical trials, cord blood, cord tissue and bone marrow derived MSCs have resulted in limited improvements in communication skills, attention and electroencephalogram (EEG) findings in children with autism, however the efficacy of this treatment strategy is controversial (34-35).
To date, SCI has released both autologous and allogeneic cord blood units to Duke University Hospital, USA, for the treatment of 13 children with ischemic brain damage resulting in cerebral palsy. One child with autism has also been treated at Duke using cord blood banked at SCI. These units were infused without any further processing to extract MSCs (36).
The future
Scaled up production of extracted/expanded MSCs or their secreted products by specialist laboratories or Pharma companies is continually evolving with new technologies bringing increased therapeutic potential for “off the shelf” treatments. Furthermore, on a more individual level, treatment using one’s own MSCs sourced from adipose tissue or bone marrow is gaining ground as is the use of privately banked cord blood/tissue derived MSC products (37). The FamiCord group, is at the forefront of personalised ATMP solutions. We manufacture a range of ATMPs derived from various sources, including cord blood, cord tissue, and adipose tissue. Amongst the 1,800+ such treatments carried out by May 2024, 46 of these have utilised ATMP products derived from family banked cord blood or cord tissue to benefit the donor themselves or a close relative. Significant global investment in developing and supporting ground-breaking MSC based therapies via research and controlled clinical trials is enhancing our ability to exploit the potential of these valuable cells as a promising therapeutic tool to treat or augment standard therapies in a range of debilitating conditions. Regenerative medicine focussing on MSC based products is projected to become a realistic option in 21st century medicine.
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