Transplantation of Human Adipose Tissue-Derived Multilineage Progenitor Cells Reduces Serum Cholesterol in Hyperlipidemic Watanabe Rabbits

Abstract

Familial hypercholesterolemia (FH) is an autosomal codominant disease characterized by high concentrations of proatherogenic lipoproteins and premature atherosclerosis secondary to low-density lipoprotein (LDL) receptor deficiency. We examined a novel cell therapy strategy for the treatment of FH in the Watanabe heritable hyperlipidemic (WHHL) rabbit, an animal model for homozygous FH. We delivered human adipose tissue-derived multilineage progenitor cells (hADMPCs) via portal vein and followed by immunosuppressive regimen to avoid xenogenic rejection. Transplantation of hADMPCs resulted in significant reductions in total cholesterol, and the reductions were observed within 4 weeks and maintained for 12 weeks. (125)I-LDL turnover study showed that the rate of LDL clearance was significantly higher in the WHHL rabbits with transplanted hADMPCs than those without transplanted. After transplantation hADMPCs were localized in the portal triad, subsequently integrated into the hepatic parenchyma. The integrated cells expressed human albumin, human alpha-1-antitrypsin, human Factor IX, human LDL receptors, and human bile salt export pump, indicating that the transplanted hADMPCs resided, survived, and showed hepatocytic differentiation in vivo and lowered serum cholesterol in the WHHL rabbits. These results suggested that hADMPC transplantation could correct the metabolic defects and be a novel therapy for inherited liver diseases.

Spermine Treated-Adipose Tissue-Derived Multi-Lineage Progenitor Cells Improve Left Ventricular Dysfunction in a Swine Model of Chronic Myocardial Infarction

“…In a series of studies, we have characterized hADMPCs as a novel and minor cell population in human adipose tissues and reported that these cells have stem cell properties including their ability to be reprogrammed in situ into cardiomyocytes in rats with MI and into hepatocyte-like cells in the rabbit hepatic parenchyma [9][10][11][12]. Based on their advantages, hADMPCs are promising source of cells for cell therapy.…”

“…Adipose tissue samples were resected from 5 human subjects Isolation of hADMPCs and spermine-treatment hADMPCs were prepared as described in detail previously [9][10][11][12]14,15]. Briefly, the resected excess adipose tissue was minced and then digested at 37°C for 1 h in Hank's balanced salt solution (HBSS, GIBCO Invitrogen, Grand Island, NY) with Liberase (Roche Diagnostics, Germany).…”

“…MSCs can be obtained from bone marrow but also easily from adipose tissue [7,8]. In a series of publications, our group reported that adipose tissue-derived multi-lineage progenitor cells (ADMPC), which met the criteria of mesenchymal stem cells [9], could be reprogrammed into hepatocytes both in vitro and in vivo [10,11]. However, human ADMPCs (hADMPCs) per se could not survive in cardiac parenchyme longer duration after transplantation and not differentiate into cardiomyocytes in vivo [12].…”

Therapeutic potential of adipose tissue-derived multi-lineage progenitor cell-sheets on liver fibrosis

“…Rat ADMPCs were prepared as described previously [8][9][10]14]. Briefly, the rat inguinal adipose tissue was minced and then digested at 37°C for 1 h in Hank's balanced salt solution (HBSS, GIBCO Invitrogen, Grand Island, NY) with Liberase (Roche Diagnostics, Germany) as indicated by the manufacturer.…”

“…Recently, cell therapy has been proposed as an attractive tool for treatment of patients with severe liver fibrosis [8][9][10][11][12][13][14]. Mesenchymal stem cells, which possess certain characteristics including self-renewal, proliferation, differentiation and/or secretion of bio-active cytokines, are promising tools in cell therapy [14].…”