Mesenchymal Stem Cells & Cancer Biology

The pinnacle of biomedical research is the ongoing development of cancer medicines. The strong therapeutic potential exists when the immune system is targeted and biological processes are used to enhance the body’s response to cancer. Mesenchymal stem cells (MSCs) are a particular kind of cell that may develop into several types of tissue and play a part in tissue regeneration and repair.

Mesenchymal stem cells also have immunomodulatory properties, which are attracting a lot of interest as a prospective strategy for the development of cell and gene treatments. For instance, based on what is necessary for tissue repair, MSCs can control the inflammatory and immunological response in the body by triggering specific immune cells.

Mesenchymal stem cells, as a biological tool, have two edges. The cells can help the body during tissue regeneration, but they can also cause cancers by supporting tumour microenvironments, promoting tumour growth, and inhibiting antitumor immune reactions. Knowing the mechanisms and interactions of mesenchymal stem cells in cancer is essential for creating potent treatments because of their pleiotropic nature.

How do MSCs Communicate?

Mesenchymal stem cells require intercellular communication to carry out their regulatory function. Through the use of proteins including cytokines, chemokines, and growth factors for signalling, mesenchymal stem cells can either profoundly change the microenvironment or indirectly. By releasing extracellular vesicles, mesenchymal stem cells can also affect how the microenvironment behaves.

Extracellular vesicles (EVs) have gained increased attention in recent years from the scientific and medical communities as important mediators in MSC cell-to-cell communication. EVs are made up of a variety of components, including proteins and RNA, which can affect how cells behave biologically. Extracellular vesicles generated by mesenchymal stem cells contain molecules that can either suppress or stimulate tumour growth. For example, some microRNAs have tumour-suppressive properties, while others, such as tissue inhibitors of metalloproteases (TIMP)-1 and -2, do the opposite. As a result, the mesenchymal stem cell communication pathway is a promising target for cancer therapy and may open up previously unravelling paths for treating disease.

Cancer Stem Cells and Mesenchymal Stem Cells

Extracellular vesicles produced by mesenchymal stem cells are an important component of the tumour microenvironment because they can be used by cancer stem cells and tumour cells to interact and cause modifications to the function of other cells. For instance, when MSCs enter a tumour, they can influence the movement of cancer cells by promoting the epithelial-mesenchymal transition process, which is where cells acquire the intrusive and transient traits that are frequently seen in metastatic cancers, a more severe and dangerous form of the disease. A more accurate representation of the tumour microenvironment can be created by researchers studying the interactions between mesenchymal stem cells and cancer stem cells using 3D cell cultures, commonly known as tumorspheres, which may provide extremely helpful discoveries into cancer biology.

The impact of cell therapy and gene therapy options can be increased, they can be improved, and alternative routes can be developed with a fuller understanding of the basic mechanisms underlying cancer.

Contact us at info@kosheeka.com for further information on mesenchymal stem cells and cancer stem cells. You can also call/WhatsApp at +91-9654321400

Applications of Dental Pulp Stem Cells in Tissue Engineering

Oral tissues and organs are connected functionally in the oral cavity, which is a complex structure. Damage to one of them that is irreversible is more likely to impact the others, leading to widespread malfunction. Oral health is negatively impacted by periodontal disorders, alveolar bone resorption and tooth decay. Dental pulp stem cells have therapeutic potential in the regeneration of dental, periodontal, and oral systems.

Dental pulp stem cells (DPSCs) are neural crest-derived cells with a high capacity for differentiation across numerous cell lineages. In vitro methods can be employed to induce very rapid osteogenic or dentinogenic differentiation of DPSCs, making these cells an appealing and potential approach for future dental and periodontal therapeutic strategies. The regeneration of salivary glands and bone deformities appears to be feasible by employing DPSCs in oral-related structures.

Novel strategies using cell-free therapy with cell extracts or secretome components also show promising results, particularly as compared to cell-based approaches, the secretome is easier to collect, quantify, and store for long-term usage in numerous fields. Here are some of the applications of Dental pulp stem cells:

  • Periodontal Tissue Regeneration
    Several studies have demonstrated the use of dental pulp stem cells and periodontal ligament stem cells in periodontal diseases. DPSCs release various growth factors including enamel matrix derivatives that help in periodontal regeneration. It also helps in repairing and healing the damaged pulp-dentin complex which is the major cause of periodontal issues. In several animal studies, it has been demonstrated that the marker Wnt3a assists in preserving the vitality of the pulp and uplifts odontoblast differentiation.
  • Blood Vessel Construction
    The pulp is a vascularized and perfused tissue that contains a group of stem cells that can differentiate in multiple directions. Dental pulp stem cells are a novel strategy for treating disorders involving small blood vessels due to their vascular properties. Teeth can be treated to a variety of growth factors, including those found in myeloid stem cell prepared medium, neurotrophic factors, nerve growth factors, vascular endothelial growth factors, and glial cell-derived neurotrophic factors, among others. Various studies have found that cell markers like TGF-β, IL-1 and IL-2 enhance the anti-inflammatory and immunomodulatory properties of DPSC that ultimately help in blood vessel construction.
  • Formation of Cartilage
    Some populations of DPSCs cells taken from the pulp can express bone-specific components such as type II collagen and chitosan, and about 30% of them can be converted into chondrocytes. Furthermore, dental pulp stem cells could be differentiated into dentin, bone, and cartilage components at a preliminary phase of cell culture. Even yet, these cells might be differentiated into osteoblasts in the late stages of culture. The development of dental pulp stem cells into chondrocytes indicates that using dental pulp stem cells in tissue engineering to treat cartilage defects could be a viable option.
  • Bone Tissue Regeneration
    In vitro experiments revealed that injecting dental pulp stem cells with gelatine scaffolds could aberrantly alter bone structures, and that seed cells from bone tissue can be employed as advanced stem cells, ushering in a new era in bone tissue engineering.
  • Nerve Repair
    The use of mesenchymal stem cells derived from the pulp of human deciduous teeth in wound healing could be beneficial. Furthermore, dental pulp stem cells exert paracrine effects due to their continuous differentiation. Apart from their substantial neural differentiation potential, DPSCs produced from multiple cranial neural crest cell lineages express many factors that promote nerve and axon regeneration. The neural crest cell markers CD271 and SOX10 have been found in DPSCs, suggesting that they could be used to encourage the development of Schwann cells, which are important in peripheral nerve repair.

If you are looking for dental pulp stem cells for your research, get in touch with us at info@kosheeka.com for more information.

Mesenchymal Stem Cells- Potential Therapeutic Applications of MSCs

Mesenchymal stem cells (MSCs) are multipotent adult stem cells. Being mutipotent, MSCs can differentiate into more than one specialized cell of the body. Generally, MSCs make the different cells in skeletal tissues e.g., chondrocytes, osteoblast, adipocyte etc. In case of MSCs giving rise to other specialized cells like neurons, reprogramming of the cells with gene therapy or bioactive compounds are desired.

Mesenchymal stem cells are found in several body regions like adipose tissue, umbilical cord, and bone marrow. In the bone marrow, another type of stem cells also exist, called the hematopoietic (blood) stem cells (HSCs). The MSCs and HSCs majorly constitute the stem cell population in the bone marrow. While extracting stem cells from the bone marrow, it is common to obtain a mix of stem cells and it is crucial to isolate the MSC population for efficient research results if they are being used for clinical experiments or therapeutic studies. Although FDA approval for MSC have not yet come up in therapeutics, emergency treatments and pilot studies are ongoing to establish them as a potential therapeutic candidate.

Potential Therapeutic Applications of MSCs

Musculoskeletal Disorders: MSCs have a primary ability to differentiate into bone cells and osteoblasts and this has led to their application in several clinical trials for repairing bone defects. The therapeutic studies are mostly site-directed. Literature reference: https://www.hindawi.com/journals/sci/2018/5373294/. Other researchers have also reported the role of MSCs in cartilage repair. Cartilage covers bone ends in joints and they can wear off in cases of sports injury or osteoarthritis. Although doctors do suggest knee surgeries in musculoskeletal defects, surgeries are complicated and risky. In early intervention, MSCs have been shown to limit inflammation in the damaged areas and promote repair. Mostly autologous therapy is pursued using MSCs as it does not provoke any risk concerning graft vs host diseases. MSCs are also used in research for bioengineering purposes to make 3D scaffold models for tissue repair and bone repair. Literature reference: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895744/.

Heart and Blood vessel Repair

MSCs can also promote new blood vessel formation called neovascularization but do not form blood vessels themselves. MSCs can release endothelial growth factors that stimulate endothelial precursors (cells that can develop inner blood vessel layer). MSCs can also guide new blood vessel assembly from pre-existing endothelial cell lining. These studies on animal models report potential of MSCs to treat diseases like limb ischemia.   Literature reference: https://www.spandidos-publications.com/10.3892/mmr.2017.8059.

Mesenchymal stem cells have been widely used in stem cell research and many clinical researchers are taking up the role of MSCs for treating serious disorders of neurodegenerative, musculoskeletal, aging-related disorders. Recently, MSCs have also been reported to be beneficial in COVID-19 and post COVID-19 treatments (Literature reference: https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(20)30198-X/fulltext). More and more therapeutic studies are taking the help of MSCs currently and researchers are trying to increase cohort size of these studies to establish MSCs as a therapeutic candidate universally. KOSHEEKA helps researchers in this progress with the opportunity to procure best quality human Mesenchymal Stem Cells without any hassle. Contact us at info@kosheeka.com

Challenges and Controversies in Human Mesenchymal Stem Cell Therapy

Mesenchymal stem cells have become popular in terms of clinical interest because of their potential in stem cell transplantation. A lot of clinical trials using mesenchymal stem cells have been achieved but many are still in the pipeline under scrutiny. Mesenchymal stem cell therapy risk should be considered in terms of long-lasting observations instead of fast results. Growing evidence from recent studies strongly suggests that the release of extracellular vesicles with mRNAs, regulatory miRNAs, multiple bioactive proteins and compounds, and the production and secretion of a large number of regulatory substances promote mesenchymal stem cell differentiation and cell replacement. The main therapeutic effects of mesenchymal stem cells are now attributed to stimulation of endogenous repair processes in the injured tissues by secreted factors as well as immunomodulatory response.

MSCs secretome

The cellular heterogeneity of mesenchymal stem cells makes consistent conclusions on therapeutic potential seem difficult as results will depend on the different tissue origins as well as harvesting/ culture procedures. This complex nature also makes mesenchymal stem cells an interesting candidate for research. A major issue regarding mesenchymal stem cell therapy research is mostly inadequate culture protocols and validation of optimal isolation and culture protocols is still needed. Aside from that, this article mainly discusses the potential challenges of mesenchymal stem cell administration in vivo. In particular, we focus on graft vs host disease, cardiologic, neural, and orthopedic issues.

Mesenchymal stem cells in Graft-versus-Host Disease

Graft-versus-host disease generally accompanies allogeneic stem cell transplantation in many patients. In GvHD treatment cases, corticosteroids are used, but not effectively. Immunomodulatory properties of mesenchymal stem cells have suggested their role in GvHD treatment for patients who are unresponsive to steroids. Although the inflammatory response reduction is noticed after mesenchymal stem cell transplantation, the downregulation of immune response could augment infection chances, especially in patients receiving immunosuppressive therapy after allogeneic stem cell transplantation. It was reported that the mesenchymal stem cell infusion might also constrain antimicrobial immune response. These studies highlight that mesenchymal stem cell transplantation for GvHD prevention is relatively safe and efficient in steroid-unresponsive GvHD, but infections remain a major patient risk.

Mesenchymal stem cells in Cardiology

Since heart tissue exhibits limited endogenous potential for cell proliferation and repair, multiple stem cell-based approaches have already been in several preclinical pipelines on animal and human models for cardiovascular diseases. Adult stem cells like mesenchymal stem cells have been indicated as one of the most promising candidates for myocardial repair and regeneration. Although mesenchymal stem cells exhibit pro-chondrogenic and osteogenic differentiation potential, several studies have provided evidence that in optimal culture conditions, mesenchymal stem cells also give rise to other specialized cell types including cardiomyocytes and endothelial cells. As for the limitations and concerns, the differentiating capacity of mesenchymal stem cells into endothelial and cardiac cells in vivo has not been fully confirmed and moreover, it is hard to confirm the presence of implanted, integrated cells in vivo, due to the lack of specific mesenchymal stem cell markers. However, recent evidence strongly indicates the predominant paracrine activity of mesenchymal stem cells after transplantation, to promote cardiac cell survival, proliferation, and differentiation. These functions are promoted by mesenchymal stem cell-derived secretome and extracellular vesicles. Although mesenchymal stem cells represent a safe population of stem cells with nearly no endogenous teratogenic risks, they may potentially lead to some adverse effects. The few reported concerns are generally related to possible proarrhythmic capacity in heart tissues.

Mesenchymal stem cells in Neurology

Multiples studies are being undertaken for mesenchymal stem cell transplantation in various neurological diseases like autism, stroke, cerebral palsy, etc. However, several data show that mesenchymal stem cells are ineffective in the case of the same. In the case of amyotrophic lateral sclerosis phase I study, the results did not show significant positive outcomes by using exogenous mesenchymal stem cells implanted in the spinal cord. The main conclusion in most of the clinical trials for ALS came out as a safety assurance in terms of mesenchymal stem cell applications. In one study, where bone-marrow-derived mesenchymal stem cells were used intrathecally, beneficial outcome was visible only in few patients. In another report, intramuscularly and intrathecally transplanted mesenchymal stem cells from the bone marrow were reported safe and aided in the stimulation of autologous neurotrophic factors release. In case of stroke, the delivery route of mesenchymal stem cell infusion is crucial and one should be aware of the process to assure the safety of the patient. Some studies report that cell clump formation before injection increases with the increasing cell storage time in suspension. In addition, mesenchymal stem cells might elicit vascular obstructions after intravascular delivery if they are cultured in monolayer culture in vitro as their size increases along with the passage number. A better solution is the 3D spheroid culture in vitro which makes mesenchymal stem cells smaller again. Further research is also required to help mesenchymal stem cells cross the blood-brain barrier as this limitation makes the engrafted numbers too less as compared to the infused numbers.

Mesenchymal stem cells in Orthopedics

Numerous studies of orthopedic diseases have reported the multipotency of mesenchymal stem cells to differentiate into a variety of lineages like muscle, bone, cartilage, and tendon. Although initial assumptions were that mesenchymal stem cells exert therapeutic effects by cell replacement, recent discoveries suggest the role of paracrine functions for tissue repair and immunomodulatory properties. While many studies have been done regarding the role of mesenchymal stem cells in osteoarthritis, the results have been inconsistent and the optimal dose/ route of cell administration is still awaiting establishment. Despite studies in the field of bone and cartilage regeneration, enough randomized controlled trials are quite lacking when it comes to understanding the role of mesenchymal stem cells. Besides that, there is also a dire need for optimizing the therapeutic dose of cells, co-adjuvants, and source of harvesting.
For more information on mesenchymal stem cells, contact us at info@kosheeka.com

 

 

How Human Umbilical Cord-derived Mesenchymal Stem Cells Used In Research?

The human umbilical cord tissue was regarded as medical waste until 1991 when fibroblast-like cells were isolated from the human umbilical cord tissue. Further characterization of these cells revealed that they express adhesion molecules (CD44, CD105), integrin markers (CD29, CD51), and mesenchymal stem cell markers like SH2 or SH3. Pluripotency markers like Oct-4, SSEA-1, and SSEA-4 were also found on these cells besides the proof of differentiation into osteoblasts, chondroblasts, and adipocytes. These evidences determined the presence of human umbilical cord-derived mesenchymal stem cells. Since the first isolation of human umbilical cord-derived mesenchymal stem cells (UC-MSCs), more research was directed towards obtaining (MSCs) from the endothelial and subendothelial layer of the umbilical cord vein.

These cells were further shown to express mesenchymal stem cell markers CD29, CD13, CD44, CD49e, CD54, CD90, and HLA-I, besides having the ability to differentiate into cardiomyocytes. Some human (UC-MSCs) even show the presence of embryonic stems cell markers.

Human (UC-MSCs)

Research Application of Human Umbilical Cord-derived Mesenchymal Stem Cells (UC-MSCs)

Since their initial discovery and characterization, human (UC-MSCs) have been used in multiple cell therapies and clinical trials for targeting inflammatory disorders, cancer, neurodegenerative diseases, etc. There are over 400 registered clinical trials utilizing human (UC-MSCs). Recently, researchers have even used human (UC-MSCs) as a therapy for rheumatoid arthritis successfully to reduce related symptoms. Research studies further suggested that human (UC-MSCs) regulated patients’ autoimmune tolerance.

One of the most recent clinical trials of human (UC-MSCs) in tissue engineering application is based on the treatment of chronic skin ulcer treatment. In the study, human (UC-MSCs) in the form of bioscaffold mesenchymal stem cells are used to treat diabetic wounds owing to the anti-inflammatory, immunomodulatory and angiogenic properties. Researchers have also used human (UC-MSCs) to treat spinal cord injury in the form of bioscaffold mesenchymal stem cells to regulate the sustained release of cells at the injury site. These studies successfully showed the formation of new nerve fibers and the gain of electrophysiological activity.

Besides being a potential therapeutic tool in tissue damage disorders, human (UC-MSCs) have also been used in cancer research due to supposed anti-tumorigenic properties. In the case of Cancer Cell Lines and in-vitro models, human (UC-MSCs) are used as vehicles for targeted anti-cancer agent delivery to observe cancer cell growth inhibition.

Human umbilical cord-derived mesenchymal stem cells have become popular in clinical therapeutic research. Their accessibility and ease of cultivation make these cells an attractive tool for Stem Cell Therapy and tissue engineering besides bioscaffold-based modeling. If your lab is looking for tissue-specific stem cells, cancer cell lines, or primary cells culture, Kosheeka can help you get your hands on the best quality! Contact info@kosheeka.com with your inquiries.

Antibiotics In Cell Culture: Why To Avoid?

Antibiotics have been a routinely used component in cell cultures to prevent the growth of bacteria but several researchers doing primary cell culture have showed their interest in avoiding them for several reasons in order to save their cultures and help the cells grow happy! Researchers unanimously agree on the saying, “With good lab practice, antibiotics are not necessary”. Let us look into why antibiotics are among the less preferred cell culture components even though they efficiently prevent bacterial contamination in cultures.

Cell culture is one of the most complex domain in the biological sciences and provides an excellent model for investigating the bio-physiological processes and therapeutic response at cellular and sub-cellular levels.Cell culture medium is optimized for maintaining healthy proliferating cells to enhance research efficacy of the experiments and assays performed by researchers. But in this game, a fundamental hindrance is the occurrence of microbiological contamination (mostly bacterial contamination). Therefore, standard cell culture protocols emphasize on including the use of antibiotics like streptomycin, gentamycin etc. as media supplements to reduce the chances of contamination. However, a prevalent question keeps on bothering the research community: Are antibiotics really helpful or do they create unnecessary complications in the culture practice?

Antibiotics are not the good Samaritans in animal cell culture. These chemicals affect the metabolism of the cultured cells and affect proliferation, differentiation and gene expression of the cells, thus hampering experiment results and questioning the validity of the same. Antibiotics harm non-bacterial structures in the cells and hinders the proliferation rate of cells. Cell proliferation has been shown to improve in several cases, in the absence of antibiotics. From the 1970s to the 90s, several reports showed anti-proliferative effects of beta-lactam antibiotics (Neftel et al., 1987) and aminoglycosides (Fischer et al., 1975Cooper at al., 1990Cooper et al., 1991) on eukaryotic cell cultures but it is not always obvious for researchers and thus get overlooked.

If you find the cells in culture not growing properly or at the usual proliferative rate, always keep a point of troubleshooting related to the use of antibiotics if there are no signs of contamination in the dish or flask. The possibility of a restricted metabolism due to the use of antibiotics is a fair one. In a study, Llobet and colleagues described how antibiotics mix can affect the differentiation of human adipose-tissue derived stem cells into adipocytes and similar hindrances were reported in embryonic stem cells (Varghese et al., 2017), mesenchymal stem cells (Chang et al., 2006), primary cancer cell lines (Relier et al., 2016) and keratinocytes (Nygaard et al., 2015). Moreover, as mentioned beforehand, the use of antibiotics can significantly alter gene expression and cell signaling regulation (Ryu et al., 2017), leading to altered drug response results and deregulated cell cycle regulation.

Keeping the cell culture medium free from microorganism contamination can be well accomplished by having proper aseptic knowledge and following food lab practices, even if antibiotics are avoided for the better. For more tips on efficient primary cell culture, consult one of the leading primary cell organization Kosheeka at info@kosheeka.com

3D Bioprinting- Biomedical And Clinical Advancements

3D printing was first developed in 1984 and slowly started making its way into several domains of technology. In recent times, 3D printing advancements have paved the way for using this technology in a cost-effective and efficient manner. Since the last few years, biomedical science companies have also started figuring out how to utilize this advanced technology for lowering healthcare costs, aiding therapeutics, and manufacturing assisting devices for injury. In 3D bioprinting, biomaterials such as hydrogels are combined with viable cells and growth factors to print 3D models of tissue-like structure that mimic natural body tissue. The stem cells and primary cells requisite are generally cultivated into a bioink to ‘print’ a bio-organic structure. 3D bioprinting-based advancements in the clinical and biomedical domains have been moderately growing with time and achieving success to solve several medical problems in the future is quite a possible dream.

According to the U.S. FDA, 3D bioprinters are already being researched on for manufacturing medical equipments and surgical devices to match the patient’s body type, besides fulfilling physiological and anatomical requirements. Till date, 3D bioprinting has already been utilized for building advanced surgical instruments at a cheaper cost than conventional manufacturing technology and thus the use of 3D bioprinting has been considered to be cost effective.

Here is a look at how 3D Bioprinting developments have revolutionized Biomedical Advancements:

Bones: A Regenerative Structure

Researchers around the world are focusing on bone bioprinting to create artificial bone matrix with regenerative biomaterial. Currently, bone grafting has been used to replace damaged bones with synthetic structures but problems of mechanical integrity and regenerative capacity has been prevalent. 3D bioprinting comes to the rescue in this case as the printed bone has the exact structure needed with a regenerative and durable biomaterial like gelatin, collagen, calcium phosphate and polycaprolactone. The bioprinted bone material is capable of fusing with a patient’s natural bones gradually and replaces them eventually owing to the repair and regeneration. Repairing bone breaks and healing bone fractures or displacements exploit the use of this technology majorly and in the future, bionics can also benefit from this technology for printing bones to support artificial body structures.

Corneas: An Eye-Opening Boost

Researchers have already worked on printing artificial cornea from biocompatible decellularized corneal stroma and viable stem cells and they are gearing towards replacing the market of synthetic corneas and cornea surgeries. Synthetic cornea materials generally used synthetic polymers and recombinant collagen which at times face complications of compatibility. 3D bioprinted corneas mimic the collagen fibril lattice pattern by focusing on the hydrodynamic aspect of the natural corneas to adequately reflect the physiological and structural aspect of the native cornea.

Cartilage: Caring For Joint Care

Researchers of BioFAB3D, an Australian biofabrication center, have built a cartilage printing device called the BioPen which uses adipose-derived stem cells to produce and implant custom made cartilage scaffolds. Biopen technology is hopeful for combpatiility in treatment of human patients in the near future, with more research and clinical studies. The biopolymer matrix and mesenchymal stem cells aid the compatibility, repair, and regeneration potential.

Skin: Alternative To Great Leap In Grafting For Burn Patients

Researchers at the Wake Forest School of Medicine have designed a 3D printer to print skin cells directly on to a burn wound, thereby bypassing conventional skin grafting which may pose issues of regenerative compatibility. The 3D bioprinting technology measures the size and depth of the wound and accordingly prints hypodermal, dermal, and epidermal skin cells at the corresponding wound regions.

The possibilities of using bioprinting technology for improving biomedical advancements in the domain of organ bioimprinting and cosmetic surgeries are improving towards an endless horizon where thinking is the only limit! For more information on the applications of bioprinting and primary stem cells in clinical therapeutics, contact info@kosheeka.com

Stem Cell Therapy For COVID-19: Potential Treatment Or Fluke?

While the world awaits a much-anticipated COVID-19 vaccine to be approved and distributed globally, several treatment options with repurposed drugs and alternative therapies are being sought after against the coronavirus disease. Among these resources, stem cell therapy has become a popular candidate with reports of successful treatment in small cohorts across the world. But do these isolated success reports ensure its position as an effective approach to COVID-19 treatment or is it just a fluke to be waved off with time?

First and foremost, let us discuss briefly about stem cells and why they are being considered as a therapeutic approach. A stem cell has the ability to differentiate into specialized cell types and lineages to sustain the growth and rejuvenation of body tissues. Stem cell therapy involves utilizing these cells to repair and restore damaged tissues of the body naturally. Mesenchymal stem cells, generally used for stem cell therapy, have been shown to possess immunomodulatory functions that can prevent cytokine storm (in case of respiratory distress syndrome, which is a severity symptom of COVID-19). Therefore, stem cells are believed to develop good immune functions in the body to combat SARS-CoV2 infection.

Recent Stem Cell Therapy Reports against COVID-19

The first stem cell treatment given to a Chinese COVID-19 patient was successful and following that, a pilot study in China on 7 COVID-19 patients found that intravenous mesenchymal stem cell infusions improved patient outcomes and recovery rate was good. Later, reports of treatment from the Abu Dhabi Stem Cell Center (ADSCC) in the UAE showed good recovery in 73 patients as per the UAE health ministry press statement. The ministry pushed the study towards the initial clinical trial phase as this therapy was hypothesized to regenerate healthy lung cells and modulate immune functions to reduce the severity of COVID-19 symptoms.

In the USA, a New York hospital performed a stem cell treatment on 12 severe COVID-19 patients out of whom 10 patients were taken out from the ventilators due to positive signs of recovery. Moreover, the US Food and Drug Administration (FDA) issued approval in April 2020 for using mesenchymal stem cells under expanded access compassionate use in case of severe COVID-19 cases. Although the approval is not accepted with welcoming arms by doctors and researchers, adequate clinical trials will determine the efficiency. Currently, there are over 20 active stem cell trials for COVID-19, mostly based on mesenchymal stem cell treatment.

Potential Therapy or Fluke?

Coronavirus has the capability of affecting the immune system and causing a cytokine overreaction in the body to damage organs and tissues and leading to Acute Respiratory Distress Syndrome (ARDS), the major cause of COVID-19 mortality. Most doctors believe that stem cell therapy is safe and can be a potential treatment against COVID-19 mostly due to the immune system modulation. Coronavirus has been already reported to have mutations and therefore will keep causing problems unless a preventive measure in terms of strengthening one’s immune system can be done. This is where stem cell therapy can also work efficiently as a wall against recurrence or future infection of coronavirus rather than treat it.

However, not everybody is all optimistic towards using stem cell therapy as many doctors and researchers complain of the inadequate study numbers and success stories. Even Dr. Karen Osman, who led the New York hospital experiment treatment mentioned earlier, said that the doctor does not claim stem cell therapy to be the sole reason for the recovery of the patients and only a randomized clinical trial can authenticate that efficiency proof. While some doctors are skeptical regarding the idea of suppressing the immune system by stem cells to avoid cytokine storm as such a step could be counter-productive with more complications for future infections. 

Therefore, though stem cells have shown efficacy in the treatment of coronavirus, only further research and conclusive clinical trial data can propagate the idea of safely using stem cell therapy in case of unanimously treating COVID-19 or preventing any scene of recurrence.

Mesenchymal Stem Cells For Healing The Kidney

According to a study by the GBD Chronic Kidney Disease Collaboration (2020), the incidence of chronic kidney disease (CKD) was 697·5 million or 9.1% in 2017: an increase of 29·3% from what was reported in 1990. The loss of lives due to CKD increased by 41·5% between 1990 and 2017! CKD is a risk factor for developing cardiovascular disease and hence is a global cause of concern. The agents currently used in the clinic are not able to stall the damage to tissues seen in CKD. Another issue is the limited regenerative ability of the kidney that is not able to stop the fibrosis. This accounts for the global trend in morbidity and mortality due to CKD. Approaches to stall the kidney damage are being actively sort after. Promising results have been seen in several models of kidney disease using mesenchymal stem cells (MSCs). These results are accounted for by the ability of MSCs to secrete cytokines to modulate the immune system and secrete anti-fibrotic and anti-apoptotic factors to boost cell repair (Chung, 2019).

The” first-in-man dose-escalation study” published in 2017 showed the safety of intra-arterial infusion of autologous MSCs in Renovascular Disease. MSCs from the adipose tissue (105 or 2.5 × 105 cells/kg body weight) were administered to 14 patients along with standardized medical treatment. While the MSCs were well tolerated, an increase in renal blood flow that is normally lowered in the disease was observed 3 months after infusion that was not seen in controls who received only standardized medical treatment. Additionally, the glomerular filtration rate was stable due to stem cell treatment showing the safety and efficiency of MSCs for kidney disease.

In the case of kidney transplantation for end-stage renal disease patients, the administration of immunosuppressive agents is associated with serious adverse effects such as opportunistic infections and metabolic disorders. In the long term phase 1 study reported in Frontiers in immunology (2018), four living-donor kidney transplant patients were administered bone marrow-derived mesenchymal stromal cells. The MSCs were administered one day before transplant in 2 patients and at day 7 post-transplant in 2 patients along with basiliximab plus low-dose rabbit anti-thymocyte globulin (RATG) and low-dose cyclosporin (CsA)/mycophenolate mofetil (MMF). The graft was stable with no cancerous tissue formation or susceptibility to infections in all patients for the 5- to 7-year follow-up. 2 patients showed favorable T cell and B cell profiles; with even discontinuation of CsA in one of these patients. The safety of using MSCs to promote tolerance of grafts was hence shown opening up avenues for further studies (NCT00752479 and NCT02012153).

The efficacy and safety of MSCs continue to be shown in repeated studies to be extended to the realm of “difficult to treat” kidney disease.

References:

GBD Chronic Kidney Disease Collaboration. Global, regional, and national burden of chronic kidney disease, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. DOI:https://doi.org/10.1016/S0140-6736(20)30045-3

Chung B. H. (2019). Use of mesenchymal stem cells for chronic kidney disease. Kidney research and clinical practice38(2), 131–134. https://doi.org/10.23876/j.krcp.19.051.

Saad, A., Dietz, A. B., Herrmann, S., Hickson, L. J., Glockner, J. F., McKusick, M. A., Misra, S., Bjarnason, H., Armstrong, A. S., Gastineau, D. A., Lerman, L. O., & Textor, S. C. (2017). Autologous Mesenchymal Stem Cells Increase Cortical Perfusion in Renovascular Disease. Journal of the American Society of Nephrology : JASN28(9), 2777–2785. https://doi.org/10.1681/ASN.2017020151

Perico, N., Casiraghi, F., Todeschini, M., Cortinovis, M., Gotti, E., Portalupi, V., Mister, M., Gaspari, F., Villa, A., Fiori, S., Introna, M., Longhi, E., & Remuzzi, G. (2018). Long-Term Clinical and Immunological Profile of Kidney Transplant Patients Given Mesenchymal Stromal Cell Immunotherapy. Frontiers in immunology9, 1359. https://doi.org/10.3389/fimmu.2018.01359

Bochon, B., Kozubska, M., Surygała, G., Witkowska, A., Kuźniewicz, R., Grzeszczak, W., & Wystrychowski, G. (2019). Mesenchymal Stem Cells-Potential Applications in Kidney Diseases. International journal of molecular sciences20(10), 2462. https://doi.org/10.3390/ijms20102462

MSCs For Sepsis In Kidney Injury

One of the major causes of acute kidney injury (AKI) is sepsis: this becomes significant given that 1–35% of hospitalized patients develop AKI. In the case of general surgery, the incidence of AKI is close to 1% but this figure reaches a whopping 70% for critically ill patients accounting for in-hospital mortality of 50% in the case of multi-organ failure! (Zarbock et al, 2014).

While the exact mechanisms of this condition are yet to be unraveled in detail, the following 3 mechanisms have been shown to be involved in this: aberrant cell bioenergetics and renal microcirculation as well as inflammation. Research shows the immunomodulatory properties of mesenchymal stem cells (MSCs), especially in terms of lowering the molecules involved in inflammation, MSCs have been used in several studies to treat sepsis-associated AKI.

2014-published research by Luo and team reported the promise of using MSCs to treat in the C57BL/6 mice model. The administration of MSCs lowered the levels of serum creatinine and blood urea nitrogen levels. The levels of the molecules IL-6, IL-17, tumor necrosis factor α, interferon γ, CXCL1, CXCL2, CXCL5, CCL2, and CCL3 were all also lowered. The injection of MSCs caused the lowering of bacterial loads in the blood and neutrophil infiltration in the kidney. Overall, the survival rate of the animals that received MSCs was higher than that of the controls (saline treatment group).

Scientists Cóndor and team showed the protective role of human Wharton’s jelly-derived mesenchymal stem cells in sepsis in a rat model of sepsis. The rationale behind the experiments was that these MSCs are known to lower the levels of proinflammatory cytokines and apoptosis markers. One of the factors involved in sepsis-induced acute kidney injury is reduced levels of a protein called Klotho. The administration of MSCs boosted the levels of Klotho and other factors such as vascular endothelial growth factor. The glomerular filtration rate (GFR) that was reduced in the rat models was also improved along with an improvement in tubular function. The level of apoptosis was lowered in the kidney and the overall survival was improved showing the protective effects of MSCs in sepsis.

Given the seriousness of sepsis in intensive ward units and its grim figures, the quest is to search for a suitable and effective approach to address this condition. MSCs on account of their availability from a broad range of cells, limited ethical challenges and their ability to modulate the immune system are a promising approach to treat this critical condition.

References:

Zarbock, A., Gomez, H., & Kellum, J. A. (2014). Sepsis-induced acute kidney injury revisited: pathophysiology, prevention and future therapies. Current opinion in critical care, 20 (6), 588–595.

Horák, J., Nalos, L., Martínková, V., Beneš, J., Štengl, M., & Matějovič, M. (2017). Mesenchymal Stem Cells in Sepsis and Associated Organ Dysfunction: A Promising Future or Blind Alley? Stem cells international, 2017, 7304121.

Luo CJ, Zhang FJ, Zhang L, Geng YQ, Li QG, Hong Q, Fu B, Zhu F, Cui SY, Feng Z, Sun XF, Chen XM. Mesenchymal stem cells ameliorate sepsis-associated acute kidney injury in mice. Shock. 2014 Feb; 41(2):123-9.

Cóndor, J. M., Rodrigues, C. E., Sousa Moreira, R. d., Canale, D., Volpini, R. A., Shimizu, M. H., Camara, N. O., Noronha, I., & Andrade, L. (2016). Treatment With Human Wharton’s Jelly-Derived Mesenchymal Stem Cells Attenuates Sepsis-Induced Kidney Injury, Liver Injury, and Endothelial Dysfunction. Stem cells translational medicine, 5(8), 1048–1057.