Use of Umbilical Cord MSCs in Type 2 Diabetes

Diabetes mellitus (DM) is a metabolic disease in which hyperglycemia is observed in patients over long periods of time. It is generally classified into four major forms: gestational diabetes, maturity-onset diabetes of the young (MODY-1), type 1 diabetes mellitus, and type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is the most predominant type of DM and accounts for virtually 95% of the total cases. Is a chronic progressive disease that starts with an impairment in the insulin-sensing mechanisms culminating in insulin resistance. This is compensated initially by increased insulin production.

During the progression of the disease, pancreatic dysfunction leads to increasingly lower insulin production, impairing glucose uptake by the peripheral tissues, and as glucose continues to accumulate in the blood, chronic hyperglycemia develops and causes toxicity, insulin-dependent tissues become more desensitized to insulin action, promoting a vicious cycle of metabolic decline. 

Current Therapies for T2DM

The management of T2DM comprises a combination of lifestyle and dietary modifications with pharmacological treatment with hypoglycemic agents and antidiabetic agents. Some examples include thiazolidinediones, metformin, dipeptidyl peptidase 4 (DPP4) inhibitors, and sodium-glucose transport protein 2 inhibitors. 

Despite the improved quality of life for T2DM patients nowadays, the available pharmacological agents on the market have limited efficacy.

The Use of Umbilical Cord Stem cells 

The Umbilical cord is considered an excellent source for the isolation, culture, and expansion of MSCs. MSCs isolated from the UC are derived from an easy-access, noncontroversial, virtually inexhaustible source that would normally be discarded. 

UC-derived MSCs can be harvested noninvasively at low cost, show high proliferation rates, be cryogenically stored for long periods, exhibit hypoimmunogenic phenotypes and immune-suppressive effects.

Also, UC-MSCs express several stem cell genes and can differentiate into different mature cell types, such as neurons, bone, cardiac muscle, chondrocytes and cartilage, and adipocytes, which reinforces their multipotent nature. 

Stem cells have been highlighted because of their potential role to restore proper immune regulation, activate  β-cell regeneration, and differentiate into β-cells in vitro.

UC-MSCs and Metabolic Dysfunction

Different studies in animal models have shown the benefits of UC-MSCs in diabetes metabolic dysfunction. Zhou and colleagues observed that hUC-MSC systemic administration, in the T2DM rat model, retarded hyperglycemic progression and prevented the body weight loss. Also, serum insulin and C-peptide levels doubled after the cell treatment. The researchers also observed  an improvement of islet mass, partially tissue morphology reestablishment, and insulin secretion in the pancreas and liver of the rats. 

UC-MSCs Paracrine Effects 

In a study by Guan et al. patients transplanted with UC-MSCs showed relatively stable blood glucose levels, with some patients being insulin free after treatment, while others required a lower dose of insulin. 

Some studies have shown that MSC could differentiate into islet endocrine lineages in vitro but cannot fully differentiate into beta cells in vivo, which highlights that MSCs effects are mainly exerted through paracrine actions. 

Other compounds being used in stem cell therapies are exosomes, which are extracellular nanoparticles secreted by cells and that contain bioactive molecules including proteins, lipids and nucleic acids. UC-MSCs derived exosomes have shown potent therapeutic effects. 

After intravenous infusion of hUC-MSC-derived exosomes, T2DM animals’ blood glucose level decreased through improved peripheral insulin sensitivity and attenuating islet destruction.

UC-MSCs and Insulin sensitivity

In diabetes, UC-MSCs’ effects are also related to insulin-sensitive tissues such as liver, adipose tissue, and skeletal muscle, generally resulting in ameliorated insulin sensitivity.

In T2DM patients’ adipose tissue, chronic low-grade inflammation and hyperglycemic toxicity are important causes of insulin resistance.

A study by Chen and colleagues reported that UC-MSCs derived exosomes could improve the insulin resistance of human adipocytes. 

Wharton’s Jelly and T2DM

Wharton’s jelly is an important umbilical cord component rich in mesenchymal cells. A study by Hu et al investigated the long-term effects and safety of MSCs on T2DM treatment. The team investigated their use via infusion in human T2DM patients with a follow-up period of 36 months. 

The patients continued with their baseline treatment and were administered 2 Warthon’s jelly MSCs infusions with an interval of 4 weeks while patients in the control group were treated with a placebo. The researchers found that the infusion improved hyperglycemia and increased insulin sensitivity, decreasing the requirement for insulin and oral hypoglycemic agents. 

Human Clinical Trials 

The effect of hUC-derived cell transplantation in T2DM human patients has also been investigated. 

A study by Guan et al evaluated the use of UC-MSCs in humans using an intravenous infusion in 6 patients with T2DM, using 1 million UC-MSCs per kg of body weight. The infusion was administered twice with a 2 week interval, and during the 24 months follow-up period, the researchers observed a significant decrease of daily insulin average requirements, with 3 of the 6 patients becoming insulin-free for the whole period. Moreover, hemoglobin A1c levels significantly diminished 3 months after UC-MSC transplantation, and maintained at a stable reduced level for the whole follow-up period.

Another study by Kong and colleagues evaluated the use of UC-MSCs in 18 patients via an intravenous infusion. Fasting plasma glucose and postprandial blood glucose of the patients were significantly reduced after the treatment and plasma C-peptide levels as well. 

None of the previous studies reported major adverse events after the procedures were performed. 

Conclusions

Although the majority of studies are small samples of diabetic patients, the results found are promising. Larger studies examining the efficacy of MSCs in T2DM are still missing, but the accumulating data from animal and clinical trials is encouraging. 

At Zignagenix we use Wharton’s jelly derived MSCs for T2DM with excellent results. Patients can see an increase in their quality of life, decrease dosage utilization of insulin and a better metabolic glycemic control. The therapy is performed with high doses of mesenchymal stem cells, based on some of the previously mentioned studies, and infused intravenously combined with exosomes to increase the efficacy of the therapy. 

Source:

Azmi, S. M., Salih, M., Abdelrazeg, S., Roslan, F. F., Mohamed, R., Jie, T. J., & Shaharuddin, B. (2020). Human umbilical cord-mesenchymal stem cells: a promising strategy for corneal epithelial regeneration. Regenerative Medicine. doi:10.2217/rme-2019-0103 

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