Diabetes mellitus (DM) is a major health concern caused by either insufficient insulin production (type 1 diabetes, T1DM) or the body’s inability to use insulin effectively (type 2 diabetes, T2D).
Recently, stem cell-based therapy has shown considerable promise as a futuristic option.
There are over 400 million people who suffer from Diabetes mellitus in 2014, and these numbers have grown steadily. It is predicted that about 600 million could have it by 2045. Currently, the treatment option being given to patients is insulin therapy, to control the blood sugar, but unfortunately, it is not capable of preventing further complications, and it can also cause other issues like hypoglycemia.
The quest for better treatment is geared towards the study of the effective use of Stem Cell therapy for diabetes. The potential use of stem-cell-derived extracellular vesicles.
Pluripotent stem cells
Human pluripotent stem cells include embryonic stem cells and human induced pluripotent stem cells. Embryonic stem cells come from the inner cell mass of embryos and replicate indefinitely, it can also differentiate into any adult cell type. While the human induced pluripotent stem cells are created via reprogramming adult cells, it also comes with fewer ethical issues as one can use the patient’s stem cells also lowering the chances of immune rejection. Both will differ when it comes to their gene expression, epigenetic changes like DNA methylation, and genetic stability.
Stem cells show great promise for treating diabetes and its complications due to their ability to modulate the immune system, differentiate into various cell types, and regenerate tissues. Different types of stem cells have been tested for their potential to regenerate insulin-producing cells, including:
- Embryonic stem cells
- Induced pluripotent stem cells
- Adult stem cells such as:
- Umbilical cord blood stem cells (UCB)
- Peripheral blood mononuclear cells (PB-MNCs)
- Bone marrow mononuclear cells (BM-MNCs)
Clinical Transplantation of hPSC Differentiation Products
Transplanting insulin-producing cells (IPCs) derived from human embryonic stem cells (hESCs) faces two main challenges: the immune system attacking the cells (immunogenicity) and the risk of unwanted growths (teratogenicity). To address these, the cells need to be enclosed in a protective device and/or treated with immune-suppressing drugs.
ViaCyte’s Approach:
- VC-01 Device: ViaCyte developed an immunoprotective device that holds pancreatic progenitor cells (PECs) derived from hESCs. Tests in rodents showed that this device helped control diabetes.
- First Clinical Trial: Henry et al. and Odorico et al. conducted an initial clinical trial with 19 patients. However, outcomes varied due to issues like poor blood vessel growth into the device and hypoxia (lack of oxygen). This trial was paused to improve the device.
- Modified VC-02 Device: A new device with wider pores was created to improve oxygenation and nutrient exchange, allowing blood vessels to grow inside. However, it does not protect against the immune system, so patients need immune-suppressing drugs.
Clinical Results:
Trial by Shapiro et al.: In a study with 17 patients, six showed some insulin production six months after transplantation. However, by one year, those without measurable insulin production were removed from the study. The explanted devices showed mostly alpha cells, with few mature beta cells (which produce insulin). No significant clinical benefit was observed.
Trial by Ramzy et al.: In another study with 15 patients, total daily insulin needs were reduced, but only one patient had a 50% reduction in insulin use after one year. No patient achieved insulin independence.
These studies show that while stem cell-derived cells can be transplanted and developed into islet cells in patients, none of the patients became insulin-independent. The limited success was due to not enough cells surviving and the formation of fibrous tissue around the device. Further improvements to the implantation device are needed.
Current Status:
Stem cells are essential for tissue repair and growth in the body. Recent experiments have shown that using stem cells alone or combined with other treatments can effectively and safely treat various illnesses, including diabetes.
The most successful therapies involved transplanting bone marrow hematopoietic stem cells (BM-HSCs) for Type 1 diabetes (T1DM) and a combination of BM-MNCs and mesenchymal stem cells (MSCs) for Type 2 diabetes (T2DM). However, patients with diabetic ketoacidosis (DKA) are not suitable candidates for stem cell transplantation.
Mesenchymal stem/stromal cells (MSCs)
What Are MSCs?
- MSCs are special cells found in many tissues and can be easily grown in the lab.
- They can travel to injured areas in the body to help repair them.
- MSCs avoid immune system detection because they lack certain markers (HLA class II, CD40, CD80, CD86).
How Do MSCs Work?
- They modulate the immune system by releasing substances and through direct contact with other cells when activated by inflammation.
- Initially, it was thought that MSCs repair tissues by becoming part of the tissue themselves. However, studies show that MSCs don’t easily integrate into tissues and often die after being transplanted.
- Now, it’s believed MSCs help more through the substances they release (secretome) rather than by integrating into tissues.
Current Understanding:
- Boregowda and others suggested MSCs work both through their inherent stem cell properties and the substances they release (paracrine effects).
- Phinny et al. explained that MSCs’ stem cell properties help with cell repair and blood vessel growth, while their paracrine effects reduce inflammation and modulate the immune system.
- They found that a gene called TWIST1 can predict MSC functions. High TWIST1 levels are linked to repair functions, and low TWIST1 levels are linked to immune-modulating functions.
New Advances:
- Van Grouw and colleagues used machine learning to predict MSC potency for immunomodulation.
- They identified key substances outside (proline, phenylalanine, pyruvate) and inside (sphingomyelins) the MSCs that indicate strong immunomodulatory capabilities.
- This helps in selecting the best MSCs for specific therapeutic purposes.
Undifferentiated MSCs and Diabetes Mellitus
How MSCs Help with Diabetes:
- MSCs can travel to injured areas and help repair pancreatic islets, which produce insulin.
- They improve blood supply to these islets and can modify the immune system, making them useful for early-onset type 1 diabetes (T1DM).
Clinical Trials:
- Hu et al.: 29 patients were studied; 15 received MSCs from Wharton’s Jelly and 14 got standard treatment. MSC-treated patients needed less insulin and had higher C-peptide levels (a marker of insulin production).
- Carlsson et al.: 10 patients received their own bone marrow MSCs. After one year, their C-peptide response improved.
- Araujo et al.: 13 patients were studied; 8 received MSCs from fat tissue and vitamin D, while 5 were controls. The MSC group needed less insulin and had lower HbA1c levels (a measure of blood sugar control) after three months.
- Izadi et al.: 11 patients received their own bone marrow MSCs. Early in their T1DM diagnosis, these patients showed improved HbA1c and C-peptide levels, and a shift from inflammation-promoting to inflammation-reducing cytokines.
- Carlsson et al.: 10 patients with early T1DM received umbilical cord MSCs. The treatment group’s insulin needs didn’t change, while the control group needed more insulin.
Review of Multiple Studies:
- He et al. reviewed many studies on MSCs for diabetes. They found that MSC treatment improved HbA1c levels, but didn’t significantly change fasting glucose or C-peptide levels. However, they noted many uncertainties
- due to different sources and doses of MSCs and the small number of patients.
- While MSCs show potential for treating early-onset T1DM, more high-quality, large-scale studies are needed to confirm their effectiveness.
Positive Impacts of MSC Therapy:
- Multiple Sources: MSCs can be taken from various tissues, making them widely available.
- Stored Cells: Umbilical cord MSCs can be stored and used later if needed, which is helpful for personalized treatment.
- Replication Capacity: Wharton’s jelly MSCs can replicate many times without aging, making them a promising source for IPCs.
Experimental Success:
- Humanized Mice Study: In experiments, IPCs from human MSCs were transplanted into diabetic humanized mice, normalizing their blood sugar levels without causing immune reactions.
- Immunomodulatory Effects: It’s suggested that even undifferentiated MSCs help regulate the immune system, improving outcomes.
Future Potential:
- No Need for Extra Measures: This approach might allow cell therapy without needing immune-suppressing drugs, special capsules, or genetic changes.
- Awaiting Clinical Trials: While promising in lab studies, MSC-derived IPCs have yet to be tested in human clinical trials for diabetes treatment.
Overall, stem cell therapy using MSCs shows promise for treating diabetes by creating insulin-producing cells and regulating the immune system, with various sources and potential long-term benefits.
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Lourdes Duque Baron is a remarkable individual who has made significant contributions as a stem cell advocate and multi-talented personality, even into her 70s. Her journey is not just inspiring; it’s a testament to the transformative power of stem cell therapy.
As a staunch advocate for stem cell research and its potential, Lourdes Duque Baron has been instrumental in raising awareness about the benefits of stem cell therapy for various medical conditions. Her advocacy efforts have helped shed light on the groundbreaking advancements in regenerative medicine, offering hope to countless individuals seeking innovative treatment options.
What sets Lourdes Duque Baron apart is not just her advocacy work but also her personal experience with stem cell therapy. Despite being in her 70s, she defied the odds by successfully treating her osteoporosis using stem cells.
It’s a reminder that age is no barrier to pursuing one’s passions, advocating for important causes, and embracing cutting-edge medical treatments that can enhance quality of life.
Through her advocacy and personal triumphs, Lourdes Duque Baron continues to inspire others to explore the potential of stem cell therapy and pursue their own paths to wellness and vitality.
References:
- Roglic G. WHO global report on diabetes: a summary. Int J Noncommun Dis. 2016;1:3–8. https://doi.org/10.4103/2468-8827.184853.
- Shapiro AM, Pokrywczynska M, Ricordi C. Clinical pancreatic islet transplantation. Nat Rev Endocrinol. 2017;13:268–77. https://doi.org/10.1038/nrendo.2016.178.
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- El-Badawy A, El-Badri N. Clinical efficacy of stem cell therapy for diabetes mellitus: a meta-analysis. PLoS ONE. 2016;11:e0151938. https://doi.org/10.1371/journal.pone.0151938.