Metal toxicity, resulting from lead, mercury, aluminum, and arsenic, continues to be a significant public health concern and contributes to a number of serious health issues, including damage to the central and peripheral nervous systems, compromised kidney and liver function, and damage to the cardiovascular system.
Specifically, toxic metals appear to contribute to oxidative stress in stem cells and endothelial progenitor cells (EPSs), the cells responsible for replenishing aging or damaged cells, and are an essential component for maintaining vasculature and neovascularization. The damage caused to these cells, as a result of metal toxicity, has directly contributed to vasoconstriction, hypertension, and altered gene expression.
Considering the established relationship between oxidative injury, endothelial cell dysfunction, and vascular disease, Mikirova et al. ‘s study examined the response of CD34-positive cells to chelation by DMSA. The study also compared the effectiveness of DMSA and EDTA in the chelation of toxic metals and the excretion of essential metals.
Mikirova et al. also share results related to the toxicity of lead and mercury to mesenchymal stem cells (MSCs), endothelial progenitor cells, and differentiated cells such as endothelial cells and fibroblasts. These results were obtained by comparing data obtained from 160 subjects who received oral DMSA chelation and 250 subjects who received intravenous EDTA chelation.
At the conclusion of this study, the authors were able to draw a number of conclusions, including:
Lead and mercury inhibit in vitro metabolism of MSCs and proliferation and adult differentiated cells, with MSCs demonstrating increased sensitivity to both lead and mercury.
DMSA demonstrated the ability to increase circulating CD34-positive cell numbers in vivo and is better at extracting lead and arsenic than EDTA – but is also more likely to increase extraction of certain essential minerals.
Removal of toxic metals significantly improved the number of stem cells and progenitor cells in circulation.
The authors also point out that DMSA offers improved results when compared to EDTA, for lead and arsenic chelation, but with a cost of higher extraction of essential minerals – including a fifty-five-fold increase in copper extraction (meaning copper levels must be monitored and supplemented for during chelation therapy). On the other hand, clearance of essential metals during chelation by EDTA was increased over twenty-fold for zinc and manganese.
Considering the findings of this study, the authors point out that these findings, along with data published in previous studies, provide some guidelines for the clinical use of DMSA and EDTA as chelating agents.
Mikirova et al. conclude that chelation therapy demonstrates promise for repairing damage resulting from metal toxicity and for restoring circulating stem cell populations. The authors next plan to embark on a larger scale study with the hopes of gaining more data on changes in white cell and progenitor cell numbers before and after chelation therapy.
Current estimates indicate that kidney disease currently affects over 37 million US adults and over 10% of the global population[1]. Characterized by gradual loss of function, kidney disease generally progresses over time and culminates in the inability to remove waste and excess fluid from the blood[2].
Often demonstrating little to no symptoms in its early stages, chronic kidney disease tends to demonstrate increasing and dangerous symptoms as the condition advances.
To date, treatment for chronic kidney disease has been centered around causal control as a way of slowing the progression of the condition. However, these therapeutic treatment efforts, including multidrug therapy, have demonstrated an inability to reverse the condition from progressing to end-stage renal disease (ESRD) and requiring additional therapy, dialysis, or kidney transplantation.
Considering the high cost and disruption to normal life function associated with dialysis and the severe shortage of viable kidney donors, neither dialysis nor transplant has proven to be ideal or often recommended treatment strategies. As a result, there has been renewed interest in new and more effective therapeutic options to alleviate, cure, or prevent kidney disease and to improve a patient’s survival and quality of life.
Evaluating the numerous and growing therapeutic applications associated with stem cells’ ability for self-renewal, proliferation, and differentiation, Liu et al.’s review explores the potential benefits offered toward improving renal function and supporting structural repair in those afflicted with kidney disease.
Despite the promising benefits of using stem cells to kidney repair and disease treatment demonstrated through prior preclinical study, the authors point out that certain ethical issues regarding the origin of stem cells, and specifically embryonic stem cells (ESCs) need to be addressed and overcome before clinical application of SCs.
Regardless of the stated drawbacks, Liu et. al concludes that the existing evidence demonstrates that stem cell therapy appears to be a clinically viable alternative for kidney disease, specifically for restoring normal kidney function and for progressing understanding about tissue regeneration, drug screening, and disease modeling.
Although stem cells demonstrate promise in this regard and while the immunomodulatory properties of mesenchymal stem cells (MSCs) appear to make them the most promising SC for treating kidney disease, the authors also point out that further research is needed before definitively concluding which source of SC is best suited for this application.
As a result of this review, and in an effort to realize these findings into clinical applications in the future, the authors call for larger rigorously designed clinical trials to further assist in determining the clinical efficacy of SC therapy in kidney disease – including the appropriate selection of cell types, number of SCs required, and the appropriate route of administration.
Typically understood to support hematopoiesis and to produce the cells of the mesodermal lineage, mesenchymal stem cells (MSCs) found in bone marrow, fat, and other tissues of the body, have recently been found to contain additional properties that include immunomodulator and neurotrophic effects.
Considering earlier studies that have demonstrated favorable effects of MSC treatments in a variety of conditions – including stroke, multiple sclerosis, multi-system atrophy, and amyotrophic lateral sclerosis, Petrou et al. performed this double-blind study as a way to evaluate the best way of administration and the safety and clinical efficacy of MSC transplantation – specifically in patients with active and progressive multiple sclerosis.
The response of the 48 patients with progressive multiple sclerosis and with displaying evidence of either clinical worsening or activity during the previous year in this study were evaluated after being treated intrathecally (IT) or intravenously (IV) with autologous MSCs or with sham injections. Having identified a critical and unmet need for treatment, the goal of Petrou et al.’s study was to examine the therapeutic efficacy of MSC transplantation in this specific population.
Over the course of this controlled clinical trial, participants were randomly assigned to three treatment groups and treated (either intrathecally or intravenously) with autologous MSCs or with sham injections. At the 6-month mark, the authors of this study retreated half of the patients in both the MSC-IT and MSC-IV groups with MSCs, while the remaining participants were treated with sham injections. The same process occurred with patients initially treated with sham injections; meaning that at the 6-month mark, half were either treated with MSC-IT or MSC-IV.
Prior to the start of this study, Petrou et al. established a number of primary and secondary endpoints. Predetermined primary endpoints of this study included: the safety of the MSC-IV and MSC-IT treatments and the difference among the three groups in relation to performance on the Expanded Disability Status Scale (EDSS) at 6- and 12-month intervals. Predetermined secondary endpoints included the difference between the sham-treated and MSC-IT or MSC-IV treated group in the number of relapses and the relapse rate, the number of MRI gadolinium-enhancing lesions, the annualized rate of change in the T2 lesion load on MRI, percent brain volume change, performance on a series of physical and cognitive functions, and the retinal nerve fiber layer thickness.
At the conclusion of this 14-month trial, the authors reported that the study demonstrated positive results in all predetermined primary endpoints. More specifically, throughout the course of this study, the authors discovered that significantly fewer patients experienced treatment failure in the MSC0IT and MSC-IV groups compared with those in the sham-treated group. Additionally, over the course of the following year, nearly 59% and 41% of patients treated with MSC-IT and MSC-IV exhibited no evidence of multiple sclerosis activity; this is compared with less than 10% of patients in the sham-treated group.
Significant improvements of those receiving MSC-IT treatment (compared to sham treatment) were also observed in the following: ambulation index, the sum of functional scores, 25-foot timed walk test, 9-hole peg tests, PASAT and OWAT/KAVE cognitive tests, and newer biomarkers, including retinal nerve fiber layer and motor network. The authors also report beneficial, but less significant effects were observed in the MSC-IV groups.
Although the authors report a number of limitations associated with this study, including a small number of patients in each group, the short duration of the study, and the crossover design of the study (which could have resulted in a “carry-over” effect from the first cycle of treatment), they also conclude that the clinically significant findings observed in patients with progressive multiple sclerosis who were previously unresponsive to traditional or conventional therapies provide clear evidence of short-term efficacy and possible indications of neuroprotection induced by administration of autologous MSCs in patients with progressive multiple sclerosis.
In addition, the authors found that intrathecal administration of MSCs appears more beneficial than intravenous, as well as the potential benefits provided by receiving repeated injections of MSCs.
As such, Petrou et al. conclude by calling for a larger phase III study to confirm these findings and as a way to further evaluate the therapeutic potential of autologous MSCs in neuroinflammatory and neurodegenerative diseases, including active progressive multiple sclerosis.
Over the past few years, data has accumulated showing the promise for cell-based therapies to help in treating Inflammatory bowel disease with stem cells. Specifically, stem cells appear to offer the opportunity to overcome several weaknesses associated with conventional therapies that have targeted perianal Crohn’s disease.
Based on these positive results, scientists and healthcare providers have become more adamant about understanding the broader role stem cells could play in the treatment of all inflammatory bowel disease. A new review published in Current Gastroenterology Reports discusses this specific issue and offers insights into the direction of stem cell research as it relates to inflammatory bowel disease.
The authors of this review discuss data from over a dozen clinical trials that have already been conducted on the impact of stem cell therapies in Crohn’s disease. Thus far, much of the success of regenerative medicine for the treatment of Crohn’s disease has been for the specific treatment of perianal Crohn’s disease, which occurs when the digestive and gastrointestinal inflammation associated with Crohn’s disease extends to the anal area.
Given the frequency with which the lining of the intestine is inflamed in inflammatory bowel disease, including both perianal Crohn’s disease and non-perianal Crohn’s disease, research efforts are focusing more and more on how stem cells may be able to combat this type of luminal disease. The authors put forth suggestions for the types of information that researchers should aim to obtain if we are to adequately treat intraluminal disease with regenerative medicine.
The potential of stem cells to address inflammatory bowel disease that has been demonstrated so far provides hope that this type of strategy will help not only patients with perianal Crohn’s disease but those with other forms of inflammatory bowel disease as well. More research should help to determine if and how these therapies can be deployed to help this patient population.
Reference: Lightner, A.L. (2019). Stem cell therapies for inflammatory bowel disease. Current Gastroenterology Reports, 21(4), 16.
For some men with prostate cancer, surgery to remove the prostate gland can be curative. The surgery to remove the entire prostate gland, called radical prostatectomy, can improve survival. If performed early, radical prostatectomy can prevent metastatic prostate cancer. While men who qualify for this surgery often jump at a chance to cure prostate cancer, radical prostatectomy comes with a price—it almost always causes erectile dysfunction. Here we talk about how Stem cells restore erectile function after prostate removal.
Even under the best surgical conditions, most men experience at least temporary erectile dysfunction after radical prostatectomy. While some men can regain erectile function by using oral ED treatments, as many as 3 out of 5 men continue to have poor erections and/or difficulty with orgasm months to years after radical prostatectomy.
In an attempt to find a way to treat this serious issue, researchers in France conducted a clinical trial to test whether mononuclear cells treatment could improve erectile function in men who had undergone radical prostatectomy and developed erectile dysfunction (INSTIN, INtra-cavernous STem-cell INjection clinical trial, NCT01089387). Mononuclear cells are a type of stem cell that can become many other cells, including nerve or blood vessels cells. The researchers collected mononuclear cells from the bone marrow of affected men and injected these cells into the patient’s own penile tissue (i.e. autologous stem cell infusion). The researchers then followed the men for 6 to 12 months to track whether the mononuclear cells helped improve erectile function.
The first phase of the phase 1/2 clinical trial was designed to assess the safety of the treatment. No patients in the trial experienced any side effects from treatment. Likewise, prostate cancer did not return any of the men within one year after treatment (and perhaps longer, the men were only followed for one year at the time of the report).
Within six months of treatment, men treated with the bone marrow stem cells had a significantly better erectile function and satisfaction with sexual intercourse. While the benefit was still present after the 12 months, the erectile function was not quite as good as it was at six months after treatment. This suggests injections may need to be repeated every six months to maintain maximal benefit.
These results are incredibly encouraging for men with erectile dysfunction caused by radical prostatectomy. While future clinical trials should contain a control group and larger numbers of men, these phase 1/2 clinical trial results pave the way for such research. These findings also suggest men who have life-saving prostate cancer surgery may be able to regain erectile function after surgery through stem cell treatment.
Reference: Yiou, R. et al. (2017). Intracavernous Injections of Bone Marrow Mononucleated Cells for Postradical Prostatectomy Erectile Dysfunction: Final Results of the INSTIN Clinical Trial. European Urology Focus. 2017 Dec;3(6):643-645.
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