Umbilical Cord Mesenchymal Stromal Cell With Autologous Bone Marrow Cell Transplantation in Established Type 1 Diabetes: A Pilot Randomized Controlled Open-Label Clinical Study to Assess Safety and Impact on Insulin Secretion

Abstract

OBJECTIVETo determine the safety and effects on insulin secretion of umbilical cord (UC) mesenchymal stromal cells (MSCs) plus autologous bone marrow mononuclear cell (aBM-MNC) stem cell transplantation (SCT) without immunotherapy in established type 1 diabetes (T1D). RESEARCH DESIGN AND METHODSBetween January 2009 and December 2010, 42 patients with T1D were randomized (n = 21/group) to either SCT (1.1 3 10 6 /kg UC-MSC, 106.8 3 10 6 /kg aBM-MNC through supraselective pancreatic artery cannulation) or standard care (control). Patients were followed for 1 year at 3-month intervals. The primary end point was C-peptide area under the curve (AUC C-Pep ) during an oral glucose tolerance test at 1 year. Additional end points were safety and tolerability of the procedure, metabolic control, and quality of life. RESULTSThe treatment was well tolerated. At 1 year, metabolic measures improved in treated patients: AUC C-Pep increased 105.7% (6.6 6 6.1 to 13.6 6 8.1 pmol/mL/180 min, P = 0.00012) in 20 of 21 responders, whereas it decreased 7.7% in control subjects (8.4 6 6.8 to 7.7 6 4.5 pmol/mL/180 min, P = 0.013 vs. SCT); insulin area under the curve increased 49.3% (1,477.8 6 1,012.8 to 2,205.5 6 1,194.0 mmol/mL/180 min, P = 0.01), whereas it decreased 5.7% in control subjects (1,517.7 6 630.2 to 1,431.7 6 441.6 mmol/mL/180 min, P = 0.027 vs. SCT). HbA 1c decreased 12.6% (8.6 6 0.81% [70.0 6 7.1 mmol/mol] to 7.5 6 1.0% [58.0 6 8.6 mmol/mol], P < 0.01) in the treated group, whereas it increased 1.2% in the control group (8.7 6 0.9% [72.0 6 7.5 mmol/mol] to 8.8 6 0.9% [73 6 7.5 mmol/mol], P < 0.01 vs. SCT). Fasting glycemia decreased 24.4% (200.0 6 51.1 to 151.2 6 22.1 mg/dL, P < 0.002) and 4.3% in control subjects (192.4 6 35.3 to 184.2 6 34.3 mg/dL, P < 0.042). Daily insulin requirements decreased 29.2% in only the treated group (0.9 6 0.2 to 0.6 6 0.2 IU/day/kg, P = 0.001), with no change found in control subjects (0.9 6 0.2 to 0.9 6 0.2 IU/day/kg, P < 0.01 vs. SCT). CONCLUSIONSTransplantation of UC-MSC and aBM-MNC was safe and associated with moderate improvement of metabolic measures in patients with established T1D.

Recipient Glycemic Micro-environments Govern Therapeutic Effects of Mesenchymal Stem Cell Infusion on Osteopenia

“…Particularly, severe osteoporosis could develop in T1D, which is also recognized as a chronic autoimmune disorder characterized by hypoinsulinemia and hyperglycemia 37, 38. MSC therapy based on systemic infusion has been proved effective in reconstructing the damaged islets and reverting hyperglycemia both in animal and in human researches, while little is known about the potential improvements in complicated lesions 25, 26, 73, 74. Interestingly, despite INS-based intensive glycemic control in T1D, complications may still persist and progress after even transient hyperglycemia 51, 75.…”

Adult muscle-derived stem cells engraft and differentiate into insulin-expressing cells in pancreatic islets of diabetic mice

“…Whereas mesenchymal stem cells derived from bone marrow and defined as a stromal cell population have been extensively investigated [13, 20, 21], the muscle stem cell population we have examined here was isolated and purified on the basis of its lower adherence to plastic and even collagen-coated dishes [25]. Such low adherence properties may favor a higher migration capacity after systemic injection, and skeletal muscle displays a number of essential characteristics that make it a potentially ideal source of stem cells for direct use in vivo .…”

“…Such an approach was recently investigated using bone marrow-derived mesenchymal stem cells [20] and umbilical cord-derived mesenchymal stem cells [21]. …”

Efficacy and Safety of Autologous Bone Marrow Mesenchymal Stem Cell Transplantation in Patients with Diabetic Retinopathy

“…Most DR clinical trials conducted to date have focused on improving local circulation and metabolism, while ignoring the improvement in general condition [8,26,28]. Moreover, previous trials investigating MSC for patients with DR did not report retinal changes, although most showed an improvement in glucose metabolism [16,29,30]. Herein, we describe the outcomes of ABMSC transplantation in patients with DR, including changes in glucose metabolism, immune function, visual function, and retina microcirculation.…”