Adoptive Transfer of Syngeneic Bone Marrow-Derived Cells in Mice with Obesity-Induced Diabetes

Abstract

There are conflicting data regarding the effects of transplantation of bone marrow-derived cells (BMDCs) on the severity of diabetes. We therefore inquired whether the competence of BMDCs is preserved on adoptive transfer into diabetic (db/db) mice and how the adoptive transfer of BMDCs affects vascular and metabolic abnormalities in these mice. Recipient db/db mice received infusions of BMDCs prepared from either db/db or non-diabetic heterozygout mice (db/m) mice and effects on endothelium-dependent relaxation, insulin sensitivity, and renal function were evaluated. Recipients of BMDCs from db/m, but not db/db donors showed better glucose control, exhibited striking improvement in endothelium-dependent relaxation in response to acetylcholine, and had partially restored renal function. Improved glucose control was due to enhanced insulin sensitivity, most likely secondary to improved vascular function. Enhanced apoptosis of endothelial progenitor cells under oxidative stress, as well as decreased endothelial progenitor cell numbers were responsible for the apparent functional incompetence of BMDCs from db/db donors. Treatment of db/db mice with Ebselen restored the resistance of both BMDCs and endothelial progenitor cells to oxidative stress , improved acetylcholine-induced vasorelaxation , and reduced proteinuria in db/db recipients of BMDC transplantation. In conclusion, infusion of BMDCs obtained from db/m donors to db/db recipient mice benefited macrovascular function, insulin sensitivity, and nephropathy. BMDCs obtained from db/db mice were functionally incompetent secondary to the increased proportion of apoptotic cells on oxidative stress challenge; their competence was restored by

Critical Role of the Nitric Oxide/Reactive Oxygen Species Balance in Endothelial Progenitor Dysfunction

“…Interestingly, niacin therapy improved the capacity of HDL to stimulate endothelial NO, reduced superoxide production, and promoted EPC-mediated endothelial repair (87). Transplantation of bone marrow-derived progenitor cells from healthy into diabetic mice enhanced insulin sensitivity, improved acetylcholine-dependant endothelial relaxation, and partially restored endothelial function (14). Oxidized LDL compounds lead to eNOS downregulation in mature endothelium to induce endothelial dysfunction.…”

Endothelial Sirtuin 1 Deficiency Perpetrates Nephrosclerosis through Downregulation of Matrix Metalloproteinase-14

“…Stress-induced premature senescence (SIPS) of vascular endothelial cells contributes to microvascular rarefaction and SIPS of endothelial progenitor cells impedes microvascular regeneration. [1][2][3][4][5][6][7][8][9][10][11] Microvascular rarefaction, particularly of the peritubular capillary network, has been construed as one of the major factors contributing to the progression of renal diseases. 12,13 One of the mechanisms of SIPS has been identified as a depletion of sirtuin 1 (SIRT1), an NAD-dependent deacetylase that undergoes cathepsin-mediated cleavage as a result of stress-induced increase in lysosomal membrane permeability.…”

Dysfunctional Endothelial Progenitor Cells in Chronic Kidney Disease

“…Our recent studies showed that bone marrow-derived cells (BMDCs) and bone marrow-derived EPCs from db/db mice with metabolic syndrome and diabetes were functionally incompetent, whereas adoptive transfer of BMDCs from syngeneic nondiabetic controls significantly improved vasculopathy, insulin sensitivity, and renal function in db/db recipients. 23 Specifically, the development of type 2 diabetes and vasculopathy associated with reduced stress tolerance for EPCs, increased frequency of apoptosis, and premature senescence. 23 There is no clearcut definition of stem cell incompetence.…”