Human umbilical cord blood cells and diabetes mellitus: recent advances.

Stem cell therapy for patients with diabetes is an area of great interest to both scientists and clinicians. Human umbilical cord blood cells (HUCBCs) are being increasingly used as a source of stem cells for cell-based therapy for diabetes because these cells can differentiate into pancreatic islet ß-cells. Administration of HUCBCs has been shown to lower blood glucose levels in diabetic animal models. The use of autologous HUCBC transfusion in type 1 diabetic children has not shown any benefit. However, "Stem Cell Educator" therapy has shown promise in long term lowering of blood glucose levels in both type 1 and type 2 diabetic patients. In this review, we will briefly discuss recent advances in HUCBC therapy in the treatment of diabetes and some of its complications.

Human umbilical-cord-blood mononucleated cells enhance the survival of lethally irradiated mice: dosage and the window of time.

The purpose of this study was to evaluate the window of time and dose of human umbilical-cord-blood (HUCB) mononucleated cells necessary for successful treatment of radiation injury in mice. Female A/J mice (27-30 weeks old) were exposed to an absorbed dose of 9-10 Gy of (137)Cs γ-rays delivered acutely to the whole body. They were treated either with 1 × 10(8) or 2 × 10(8) HUCB mononucleated cells at 24-52 h after the irradiation. The antibiotic Levaquin was applied 4 h postirradiation. The increased dose of cord-blood cells resulted in enhanced survival. The enhancement of survival in animals that received 2 × 10(8) HUCB mononucleated cells relative to irradiated but untreated animals was highly significant (P < 0.01). Compared with earlier studies, the increased dose of HUCB mononucleated cells, coupled with early use of an antibiotic, extended the window of time for effective treatment of severe radiation injury from 4 to 24-52 h after exposure.

Defective neuromuscular transmission in the SOD1 G93A transgenic mouse improves after administration of human umbilical cord blood cells.

To assess the effect of human umbilical cord blood (hUCB) transplantation on neuromuscular transmission in SOD1(G93A) transgenic mice, we studied the probability of neuromuscular transmission (PNMT), a relevant physiological indicator of motor nerve function, in 3 SOD1(G93A) mice transplanted with hUCB and compared to PNMT in 4 SOD1(G93A) mice without cell transplantation and 3 non-mutant SOD1 transgenic mice. For preparations isolated from non-mutant SOD1 transgenic mice, PNMT was 0.93 and 0.84 during the first 5 s of 70 and 90 Hz trains, respectively. PNMT gradually declined to 0.77 and 0.42 at the end of the trains. In striking contrast, PNMT for preparations from non-treated mutant SOD1(G93A) mice was 0.52 and 0.36 in the first 5 s of 70 and 90 Hz trains, respectively (p<0.05). Treatment with hUCB significantly (p<0.05) improved PNMT in SOD1(G93A) preparations. That is, the initial 5 s PNMT was 0.88 and 0.68 for the 70 and 90 Hz stimuli, respectively. We concluded that hUCB transplantation significantly improved PNMT for muscles removed from SOD1(G93A) mice. Testing PNMT in the SOD1(G93A) mouse model could be used as a simple in vitro protocol to detect a positive cellular response to therapeutic interventions in ALS.

Human umbilical cord blood as an emerging stem cell therapy for diabetes mellitus.

Cellular therapy for patients with diabetes is receiving great attention among scientists and clinicians. Bone marrow is considered one of the rich sources of stem cells. However, the limited availability of bone marrow donors precludes its use for all the suitable patients. Human umbilical cord blood (HUCB) is being increasingly used as an alternative source of stem cells for cell-based therapy for malignant and nonmalignant diseases. HUCB is preferred to bone marrow because of its easy availability, low potential for graft-versus-host disease and tumorigenicity as well as infectious complications. Furthermore, no immunosuppression is required. In vitro and in vivo studies have shown that HUCB-derived stem cells can differentiate into insulin-secreting ß-cells. Administration of HUCB cells has been shown to improve blood glucose levels in diabetic animals. The first use of autologous HUCB transfusion in type 1 diabetic children is showing promise in reducing the daily requirement of insulin dose and the maintenance of near normoglycemia over a short period of time. The time has come for more clinical trials using autologous and allogenic cord blood transfusion to treat diabetes mellitus.

The effect of human cord blood therapy on the intestinal tract of lethally irradiated mice: possible use for mass casualties.

PURPOSE: To evaluate the recovery of the gastrointestinal tract in lethally irradiated mice treated with human cord blood and antibiotics. MATERIALS AND METHODS: A/J mice were randomly assigned to seven study groups, including groups exposed to acute 9 Gy from (137)Cs gamma-rays to the whole body. Four hours after irradiation, exposed mice were treated with either cord blood nucleated cells, Levaquin, or a combination of both. Weight gain/loss and survival were monitored for 2 months. Upon death or euthanasia, the organs were prepared for molecular and histological analyses. RESULTS: Whereas irradiated mice (n = 9) lived 6-15 days, approximately 60% of irradiated mice that received the combined treatment (n = 7) survived more than 50 days. None of the treated animals developed Graft versus Host disease. All animals lost weight after irradiation; however, the 50(+) days-survivors (n = 4) gained on average approximately 1.8 g over their initial weight. Whereas hemorrhagic bone marrow and large areas of transmural necrosis were observed in the bowel of the irradiated mice, the 50(+) days-survivors showed recovery of the bone marrow. They behaved normally and had significant but incomplete recovery of the intestinal and colonic mucosa. Human DNA was detected in their organs, particularly in the large intestine. CONCLUSION: Red cell-depleted cord blood transfusions combined with antibiotic treatment contribute to bone marrow and gastrointestinal recovery in high dose-irradiated mice, and may be an available therapy for mass casualties during radiological emergencies.

Administration of human umbilical cord blood cells produces interleukin-10 (IL-10) in IL-10 deficient mice without immunosuppression.

Recent studies from our laboratory have shown that intravenous administration of human umbilical cord blood (HUCB) mononuclear cells to mice improved blood glucose levels, survival, atherosclerosis and prostate cancer. In this study, we examined the effect of HUCB cells on the production of IL-10 levels in IL-10 knockout mice. It has been proposed that administration of IL-10 may be beneficial in the treatment of inflammatory bowl disease. The results show that mice treated with HUCB cells (100 x 10(6)) produce IL-10, as demonstrated by both qualitative and quantitative analyses, and that the levels of this cytokine persisted until the mice were sacrificed (5.5 months after administration). Immunohistochemical staining of the intestine using HuNu antibody cocktail demonstrated the presence of HUCB cells in the knockout mouse. Although the mice did not receive any immunosuppression, there was no evidence of graft-versus-host disease. Our data suggest that HUCB cells are capable of producing IL-10, and the use of these cells or HUCB may be indicated in the treatment of certain human diseases.

Administration of human umbilical cord blood to low birth weight infants may prevent the subsequent development of type 2 diabetes.

Both epidemiological and experimental studies have shown that impaired growth in utero due to maternal malnutrition, resulting in low birth weight, is associated with a high incidence of glucose intolerance, insulin resistance, and type 2 diabetes in adult life. Maternal malnutrition is a worldwide problem and unavoidable; therefore, prevention of type 2 diabetes in low birth weight infants who reach adulthood is difficult to achieve. Administration of human umbilical cord blood (HUCB) mononuclear cells into type 1 and type 2 diabetic mice has been shown to improve both their blood glucose levels and survival. It has also been shown that the progenitor cells derived from HUCB improve not only glycemia but also other disease conditions, including systemic lupus erythematosis, amyotrophic lateral sclerosis, Alzheimer's disease, stroke, brain damage in animals and certain malignancies in humans. Transfusion of unrelated HUCB, although abundantly available, is underutilized as a therapeutic agent. Therefore, we propose the hypothesis that transfusion of HUCB to low birth weight infants be considered a therapeutic modality to prevent the development of type 2 diabetes in their adulthood.

Administration of human umbilical cord blood cells delays the onset of prostate cancer and increases the lifespan of the TRAMP mouse.

Stem cell transplantation to improve the onset and survival of animals or humans with prostate cancer has not been studied adequately. In this study, we examined whether intravenous administration of human umbilical cord blood (HUCB) mononuclear cells into TRAMP (transgenic adenocarcinoma of the mouse prostate) mice can delay the onset of prostate cancer and improve survival of these mice before and after the development of cancer. Twenty TRAMP mice were randomly divided into 2 groups. One group of 10 mice received 200 x10(6) HUCB mononuclear cells retro-orbitally into the venous plexus at the age of 6 weeks. Another group of 10 mice did not receive HUCB cells and served as control mice. The presence of tumor was detected by abdominal palpation, which was confirmed by biopsy. When 4 of the 10 control mice developed the tumor, they were treated with the same dose of HUCB cells. Either at the time of death or sacrifice, various tissues were examined for the presence of HUCB cell total RNA by reverse transcriptase PCR. Also, the tissues were examined histologically for the presence of metastasis and carcinoma. Kaplan-Meier survival plots were used to assess the lifespan of the mice. The data show that the control mice developed the tumor much earlier than the treated mice (control vs treated: 238+/-38 vs 311+/-40 days; P<0.001). Also, transplantation of HUCB cells either before or after the development of tumor significantly increased the life span compared to that of control mice. Persistence of human RNA either in blood or spleen was associated with prolonged survival. No graft vs host disease was observed in any of the mice. In conclusion, transplantation of HUCB mononuclear cells via intravenous administration into TRAMP mice retards not only the development of prostate cancer but also increases the lifespan of these mice.

Prevention of atherosclerosis in LDL receptor-mutant mice by human umbilical cord blood cells.

Previous studies have shown that congenic bone marrow transplantation into apolipoprotein E-deficient mice prevented hypercholesterolemia and atherosclerosis. In this study, we examined the effect of intravenous administration of human umbilical cord blood (HUCB) mononuclear cells on the progression of atherosclerosis in male homozygous mice that had mutation in the low-density lipoprotein receptor (Ldlr(tm1Her) mutation mice). In addition, the effect of human breastmilk alone as well as the combination of HUCB cells and breastmilk was studied on the prevention of atherosclerosis in these mice. In all groups of mice, atherosclerosis was predominant in the ascending aorta, but the rest of the aorta had variable evidence of atherosclerosis. Treatment of mice with HUCB cells significantly ameliorated the development of atherosclerosis in the ascending aorta, as compared with untreated mice; whereas breastmilk alone did not have any significant effect. A similar beneficial effect was observed with the combination therapy, which could be attributed only to HUCB cell treatment. There was no beneficial effect of treatment on the thoracic and abdominal aorta. Thus, early administration of HUCB cells prevents the progression of atherosclerosis in the ascending aorta of mice that are prone to the development of atherosclerosis. This beneficial effect occurred without any immunosuppression and graft-vs-host disease.

Effect of human umbilical cord blood cells on glycemia and insulitis in type 1 diabetic mice.

Several studies have shown that transplantation of embryonic stem cells into diabetic animals either improved or normalized blood glucose levels. In this study, we examined the dose-dependent effect of early (prediabetic stage) intravenous administration of human umbilical cord blood (HUCB) mononuclear cells on blood glucose levels, survival, and insulitis in nonobese diabetic (NOD) mice with autoimmune type 1 diabetes. The results show that mice treated with HUCB cells significantly lowered their blood glucose levels and increased their lifespan, as compared with untreated mice. Also, a significant reduction in insulitis was observed in treated than in untreated mice. The mice that received the highest dosage (200 x 10(6)) of cells had greater reduction in blood glucose levels and the degree of insulitis than the mice that received lower dosage (100-150 x 10(6)) of cells. Prolonged lifespan in the former group of mice seems to be related to better control of blood glucose levels. Thus, administration of HUCB cells in the prediabetic stage without any immunosuppression improves type 1 diabetes by protecting the islets from insulitis in NOD mice.

Transplantation of human umbilical cord blood cells improves glycemia and glomerular hypertrophy in type 2 diabetic mice.

Recent in vitro and in vivo studies have shown that either animal- or human-derived embryonic stem cells can differentiate into insulin-secreting cells and lower blood glucose levels. However, studies utilizing human umbilical cord blood (HUCB) mononuclear cells to improve blood glucose levels in diabetic animals have received little attention. In this study, we examined the effect of transplanted HUCB mononuclear cells on blood glucose levels, survival, and renal pathology in obese mice with spontaneous development of type 2 diabetes. The results show that injection of HUCB mononuclear cells into orbital plexus of mice caused improvement not only in blood glucose levels and survival rate but also normalization of glomerular hypertrophy and tubular dilatation. Thus, transplantation of HUCB mononuclear cells appears to be another modality of stem cell therapy in diabetes mellitus.

Parkinson's disease mice and human umbilical cord blood.

In 1995, it was suggested that immature stem cells (Berashis Cells) existing in human cord blood might have an ameliorating effect on such neurological diseases as Alzheimer's, amyotrophic lateral sclerosis and Parkinson's disease. Since these predictions, we have been able to successfully extend the length of life of mice with amyotrophic lateral sclerosis [B6SJL-TgN(SOD1-G93A)IGUR], Huntington's Disease (B6CBA-TgN(H.Dexon1)62Gpb and Alzheimer's mice [Tg(HuAPP695.SWE)2576]. Recently we expanded the studies to include mice with Parkinson's Disease. 32 mice, 6-12 weeks old B6CBACa-AW-J/A-Kcnj6 were obtained from Jackson Laboratory, Bar Harbor, Maine. The mice were divided into 3 groups: (A) 10 untreated control mice, (B) 10 mice treated with 5.6 x 10(6) congenic bone marrow mononuclear cells and (C) 12 mice receiving 100-110 x 10(6) HUCB mononuclear cells intravenously. No immunosuppression was used. When 50% of the controls were dead only 1 of the 10 mice receiving congenic marrow and 2 out of 12 mice that received cord blood mononuclear cells were dead. This preliminary study was terminated when the animal's were 200 days old, at that time one out of 10 controls was alive. Out of 10 mice that received congenic bone marrow, 2 were alive. Out of 12 mice that received megadoses of cord blood mononuclear cells 4 were alive. Survival curve of mice that had congenic marrow had a p value of <.05; the survival curve of mice receiving cord blood mononuclear cells had a p value <.001 (Fig 1) compared to controls. Human umbilical cord blood mononuclear cells significantly delayed the onset of symptoms and death of Parkinson's disease mice. This effect was greater than that produced by congenic bone marrow cells.

NOD/LtJ type I diabetes in mice and the effect of stem cells (Berashis) derived from human umbilical cord blood.

Previously we have successfully delayed the onset of vasculitis and death in MRL Lpr/Lpr mice that are considered to have an autoimmune disease similar to human lupus erythematosus. Likewise, with the use of megadose human umbilical cord blood mononuclear cells, we were able to delay the onset of symptoms and death in SOD1 mice that carry a transgene for amyotrophic lateral sclerosis, considered by some to be an autoimune disease. A similar approach was utilized with NOD/LtJ type 1 diabetic mice. By administering megadoses of human umbilical cord blood mononuclear cells we were able to ameliorate the disease and improved the life span. This occurred to a greater extent than with bone marrow obtained from congenic mice. No immunosuppression was utilized in this study. This study raises the possibility of utilizing human cord blood mononuclear cells in conjunction with pancreatic islet transplantation.