Dynamics of Sex Hormones in Men with Diabetes Mellitus After Autologous Mesenchymal Stem Cell Transplant.

OBJECTIVES: Our goal was to determine levels of sex hormones in men with type 1 diabetes mellitus and type 2 diabetes mellitus after autologous mesenchymal stem cell transplant. MATERIALS AND METHODS: We examined 10 male patients (32-56 years old) with type 1 diabetes mellitus and type 2 diabetes mellitus, whom we subsequently divided into 2 groups and examined. Group 1 comprised 5 male patients who received autologous mesenchymal stem cell transplant (cells were obtained from patient's iliac crest and cultured for 3-4 weeks) by intravenous infusion. Group 2 comprised 5 male patients (control group) who were on hypoglycemic tablet therapy or insulin therapy. The quantity of autologous mesenchymal stem cells infused was 95 × 106 to 97 × 106 cells. We analyzed levels of testosterone, luteinizing hormone, estradiol, and glycated hemoglobin in patients both before and 3 months after the autologous mesenchymal stem cell transplant procedure. RESULTS: In men with type 1 diabetes mellitus and type 2 diabetes mellitus, autologous mesenchymal stem cell transplant led to an increase in testosterone levels from 5.31 ± 2.12 to 6.33 ± 2.12 ng/mL (P = .82), a decrease in luteinizing hormone from 8.43 ± 1.25 to 5.94 ± 1.57 mIU/mL (P = .04), and a decrease in glycated hemoglobin from 9.45 ± 1.24% to 8.53 ± 1.08% (P = .25) after 3 months. The increase in testosterone in men with autologous mesenchymal stem cell transplant group of 6.33 ± 2.12 ng/mL was significant compared with men in the control group (3.9 ± 1.18 ng/mL; P = .01). CONCLUSIONS: Testosterone level increased and luteinizing hormone level decreased within 3 months after autologous mesenchymal stem cell transplant in men with diabetes mellitus.

Improving Fertility in Non-obstructive Azoospermia: Results from an Autologous Bone Mar-row-Derived Mesenchymal Stromal/Stem Cell Phase I Clinical Trial.

BACKGROUND: In this phase I clinical trial, our primary objective was to develop an innovative therapeutic approach utilizing autologous bone marrow-derived mesenchymal stromal/stem cells (BM-MSCs) for the treatment of nonobstructive azoospermia (NOA). Additionally, we aimed to assess the feasibility and safety of this approach. MATERIALS AND METHODS: We recruited 80 participants in this non-randomized, open-label clinical trial, including patients undergoing NOA treatment using autologous BM-MSCs (n=40) and those receiving hormone therapy as a control group (n=40). Detailed participant characteristics, such as age, baseline hormonal profiles, etiology of NOA, and medical history, were thoroughly documented. Autotransplantation of BM-MSCs into the testicular network was achieved using microsurgical testicular sperm extraction (microTESE). Semen analysis and hormonal assessments were performed both before and six months after treatment. Additionally, we conducted an in-silico analysis to explore potential protein-protein interactions between exosomes secreted from BM-MSCs and receptors present in human seminiferous tubule cells. RESULTS: Our results revealed significant improvements following treatment, including increased testosterone and inhibin B levels, elevated sperm concentration, and reduced levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and prolactin. Notably, in nine patients (22.5%) previously diagnosed with secondary infertility and exhibiting azoospermia before treatment, the proposed approach yielded successful outcomes, as indicated by hormonal profile changes over six months. Importantly, these improvements were achieved without complications. Additionally, our in-silico analysis identified potential binding interactions between the protein content of BM-MSC-derived exosomes and receptors integral to spermatogenesis. CONCLUSION: Autotransplantation of BM-MSCs into the testicular network using microTESE in NOA patients led to the regeneration of seminiferous tubules and the regulation of hormonal profiles governing spermatogenesis. Our findings support the safety and effectiveness of autologous BM-MSCs as a promising treatment modality for NOA, with a particular focus on the achieved outcomes in patients with secondary infertility (registration number: IRCT20190519043634N1).

Mesenchymal stromal/stem cells and their exosomes for restoration of spermatogenesis in non-obstructive azoospermia: a systemic review.

Stem cells have been introduced as new promising therapeutic agents in treatment of degenerative diseases because of having high differentiation potential while maintaining the ability to self-replicate and retaining features of their source cells. Among different type of cell therapies, mesenchymal stromal/stem cell (MSC) therapy is being increasingly developed as a new way to treat structural defects that need to be repaired and regenerated. Non-obstructive azoospermia (NOA) is a reproductive disease in men that causes infertility in 10% of infertile men. Based on in vitro studies, MSCs from different tissue sources have been differentiated into germ cells or gamete progenitor cells by simple methods in both male and female. On the other hand, the therapeutic effects of MSCs have been evaluated for the treatment of NOA animal models created by chemical or surgical compounds. The results of these studies confirmed successful allotransplantation or xenotransplantation of MSCs in the seminiferous tubules. As well, it has been reported that exosomes secreted by MSCs are able to induce the process of spermatogenesis in the testes of infertile animal models. Despite numerous advances in the treatment of reproductive diseases in men and women with the help of MSCs or their exosomes, no clinical trial has been terminated on the treatment of NOA. This systematic review attempts to investigate the possibility of MSC therapy for NOA in men.

Integral Hematologic Indices in the Evaluation of the Immunologic Reactivity of the Organism in a Patient With Complication of Type 1 Diabetes Mellitus: A Case of Diabetic Retinopathy After Autologous Mesenchymal Stem Cell Transplant.

The search continues for pathogenetically effective measures in autoimmune processes for a number of complications of type 1 diabetes mellitus, in particular, diabetic retinopathy. However, there are few studies of the prognostic and therapeutic values of the systemic autoimmune response in this pathology after transplant of autologous mesenchymal stem cells. Here, we present a 40-year-old patient with complications of type 1 diabetes mellitus (diabetic retinopathy) after mesenchymal stem cell transplant. Based on peripheral blood results, we were able to calculate integral hematologic parameters, allowing us to indirectly assess the patient's immune system after autologous mesenchymal stem cell transplant. One month after autologous mesenchymal stem cell transplant, we observed a positive immune response, with a 40% decrease in leukocyte intoxication index and a 22% increase from the initial lymphocyte and eosinophil ratio index values, which indicated the formation of a delayed-type hypersensitivity reaction. Two months after transplant, stem cell leukocyte intoxication index, in contrast, increased by 10%, indicating a possible metabolic shift. At the same time, changes were observed in the lymphocyte stimulation index value, which increased by 11%. This observation indicated negative immunologic reactivity, namely, poor function of factors of nonspecific resistance due to autointoxication of the organism. However, 3 months after transplant, the hematologic parameters of this patient returned to levels before treatment. The use of integral hematologic parameters can indirectly interpret parallels between immunologic reactivity and metabolic disorders in type 1 diabetes mellitus complications (diabetic retinopathy) after autologous mesenchymal stem cell transplant. These parameters could become a diagnostic indicator in the correction of pathogenetic therapy.

Autologous Mesenchymal Stem Cell Transplant in Patients with Type 1 Diabetes Mellitus.

OBJECTIVES: Our goal was to determine the efficacy of autologous mesenchymal stem cell transplant for treatment in patients with type 1 diabetes mellitus. MATERIALS AND METHODS: We examined 5 patients (4 male, 1 female; age 20-42 y) with type 1 diabetes mellitus who received autologous mesenchymal stem cell transplant (cells were obtained from the patient's iliac crest and cultured for 3-4 weeks) performed by intravenous infusion. The quantity of autologous mesenchymal stem cells infused was 95 to 97 × 106. We analyzed daily insulin dosages and leptin and glycated hemoglobin levels in patients before and 1, 2, and 3 months after their autologous mesenchymal stem cell transplant procedure. RESULTS: In patients with type 1 diabetes mellitus, autologous mesenchymal stem cell transplant led to a decrease in daily insulin dosage levels, from 63 ± 8.83 to 50.2 ± 12.1 U (P = .064) after 1 month, with significantly increased leptin levels and trend to decreased glycated hemoglobin levels, from 6.86 to 10.77 ng/mL (P = .016) and 9.11% to 8.74% (P = .84) after 3 months, respectively. CONCLUSIONS: Daily insulin dosage level decreased within 1 month and leptin levels increased significantly within 3 months after autologous mesenchymal stem cell transplant in patients with type 1 diabetes mellitus.

Infusion of autologous bone marrow derived mononuclear stem cells potentially reduces urinary markers in diabetic nephropathy.

BACKGROUND: Diabetic nephropathy (DN) is the leading cause of end-stage renal disease worldwide. Previous studies demonstrated safety and efficacy of autologous bone marrow-derived mononuclear cells (ABM-MNCs) in induced type-1 diabetes mellitus (T1DM) rats. However, the effect of ABM-MNCs on urinary markers of DN in humans is not well studied. We evaluated the therapeutic effect of ABM-MNCs on the urinary markers microalbuminuria (MAU), urinary type-IV collagen and urinary neutrophil gelatinase-associated lipocalin (uNGAL) in T1DM patients with and without nephropathy. METHODS: This prospective open-label pilot study included 15 patients with T1DM, who had completed 2 visits within 6 months. Patients were divided into two groups according to the presence (DN, n = 7) and absence of nephropathy (T1DM, n = 8). ABM-MNCs were injected at each visit as per study protocol. Routine laboratory data, diabetes tests (fasting serum C-peptide and insulin, glycated hemoglobin, fasting and postprandial glucose), 24-h MAU and urinary type-IV collagen were measured at each visit. uNGAL levels were studied before and after 3 days of ABM-MNCs infusion at each visit. RESULTS: Mean age of patients was 29.2 ± 10.4 years, 33% were male, and 27% of the overall group had hypertension. MAU was significantly reduced in the overall group (- 26.0%, p = 0.037), including in DN (- 83.2%, p = 0.021). A short-term significant reduction of uNGAL levels was observed 3 days after ABM-MNCs administration during the both the 1st visit (median 13.4 vs. 9.5 ng/ml, p = 0.027) and 2nd visit (median 8.8 vs. 6.4 ng/ml, p = 0.042) in both groups. However this reduction did not remain significant at the 6-month follow-up. Urinary type-IV collagen did not respond significantly to ABM-MNCs infusion. CONCLUSION: Infusion of autologous bone marrow-derived mononuclear cells significantly reduced levels of MAU in DN patients. Further studies with larger sample size are needed to confirm these observations.