Implanted Muscle-Derived Stem Cells Ameliorate Erectile Dysfunction in a Rat Model of Type 2 Diabetes, but Their Repair Capacity Is Impaired by Their Prior Exposure to the Diabetic Milieu.
Muscle-derived stem cells (MDSCs) and other SCs implanted into the penile corpora cavernosa ameliorate erectile dysfunction in type 1 diabetic rat models by replenishing lost corporal smooth muscle cells (SMCs) and decreasing fibrosis. However, there are no conclusive data from models of type 2 diabetes (T2D) and obesity.



To determine whether MDSCs from obese Zucker (OZ) rats with T2D at an early stage of diabetes (early diabetic SCs isolated and cultured in low-glucose medium [ED-SCs]) counteract corporal veno-occlusive dysfunction and corporal SMC loss or lipo-fibrosis when implanted in OZ rats at a late stage of diabetes and whether MDSCs from these OZ rats with late diabetes (late diabetic SCs isolated and cultured in high-glucose medium [LD-SC]) differ from ED-SCs in gene transcriptional phenotype and repair capacity.



ED-SCs and LD-SCs were compared by DNA microarray assays, and ED-SCs were incubated in vitro under high-glucose conditions (ED-HG-SC). These three MDSC types were injected into the corpora cavernosa of OZ rats with late diabetes (OZ/ED, OZ/LD, and OZ/ED-HG rats, respectively). Untreated OZ and non-diabetic lean Zucker rats functioned as controls. Two months later, rats were subjected to cavernosometry and the penile shaft and corporal tissues were subjected to histopathology and DNA microarray assays.



In vivo erectile dysfunction assessment by Dynamic Infusion Cavernosometry followed by histopathology marker analysis of the penile tissues.



Implanted ED-SCs and ED-HG-SCs improved corporal veno-occlusive dysfunction, counteracted corporal decreases in the ratio of SMCs to collagen and fat infiltration in rats with long-term T2D, and upregulated neuronal and endothelial nitric oxide. LD-SCs acquired an inflammatory, pro-fibrotic, oxidative, and dyslipidemic transcriptional phenotype and failed to repair the corporal tissue.



MDSCs from pre-diabetic rats injected into the corpora cavernosa of rats with long-term T2D improve corporal veno-occlusive dysfunction and the underlying histopathology. In contrast, MDSCs from rats with long-term uncontrolled T2D are imprinted by the hyperglycemic and dyslipidemic milieu with a noxious phenotype associated with an impaired tissue repair capacity. SCs affected by diabetes could lack tissue repair efficacy as autografts and should be reprogrammed in vitro or substituted by SCs from allogenic non-diabetic sources.
Division of Urology, Department of Surgery, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, CA, USA; Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Istvan
I
Kovanecz
Division of Urology, Department of Surgery, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, CA, USA.
Dolores
D
Vernet
Division of Urology, Department of Surgery, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, CA, USA.
Maryam
M
Masouminia
Division of Urology, Department of Surgery, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, CA, USA; Department of Medicine, Charles Drew University of Medicine and Science, Los Angeles, CA, USA.
Robert
R
Gelfand
Division of Urology, Department of Surgery, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, CA, USA.
Leila
L
Loni
Department of Medicine, Charles Drew University of Medicine and Science, Los Angeles, CA, USA.
James
J
Aboagye
Department of Medicine, Charles Drew University of Medicine and Science, Los Angeles, CA, USA.
James
J
Tsao
Division of Urology, Department of Surgery, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, CA, USA; Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Jacob
J
Rajfer
Division of Urology, Department of Surgery, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, CA, USA; Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Department of Medicine, Charles Drew University of Medicine and Science, Los Angeles, CA, USA. Electronic address: ncadavid@ucla.edu.
Nestor F
NF
Gonzalez-Cadavid
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology / Q000628:therapy*; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology; D004727:Endothelium / Q000473:pathology; D007172:Erectile Dysfunction / Q000503:physiopathology / Q000628:therapy*; D008297:Male; D032389:Myocytes, Smooth Muscle; D010413:Penis / Q000503:physiopathology; D051381:Rats; D011924:Rats, Zucker; D033581:Stem Cell Transplantation; D013234:Stem Cells
Corpora Cavernosa; Corporal Veno-Occlusive Dysfunction; Diabetes; Dyslipidemia; Fibrosis; Hyperglycemia; Myostatin; Obesity; Smooth Muscle; Stem Cell Damage