title: Smooth Muscle Progenitor Cells Derived From Human Pluripotent Stem Cells Induce Histologic Changes in Injured Urethral Sphincter.
abstract: : Data suggest that myoblasts from various sources, including bone marrow, skeletal muscle, and adipose tissue, can restore muscle function in patients with urinary incontinence. Animal data have indicated that these progenitor cells exert mostly a paracrine effect on the native tissues rather than cell regeneration. Limited knowledge is available on the in vivo effect of human stem cells or muscle progenitors on injured muscles. We examined in vivo integration of smooth muscle progenitor cells (pSMCs) derived from human pluripotent stem cells (hPSCs). pSMCs were derived from a human embryonic stem cell line (H9-ESCs) and two induced pluripotent stem cell (iPSC) lines. pSMCs were injected periurethrally into urethral injury rat models (2 × 106cells per rat) or intramuscularly into severe combined immunodeficiency mice. Histologic and quantitative image analysis revealed that the urethras in pSMC-treated rats contained abundant elastic fibers and thicker muscle layers compared with the control rats. Western blot confirmed increased elastin/collagen III content in the urethra and bladder of the H9-pSMC-treated rats compared with controls. iPSC-pSMC treatment also showed similar trends in elastin and collagen III. Human elastin gene expression was not detectable in rodent tissues, suggesting that the extracellular matrix synthesis resulted from the native rodent tissues rather than from the implanted human cells. Immunofluorescence staining and in vivo bioluminescence imaging confirmed long-term engraftment of pSMCs into the host urethra and the persistence of the smooth muscle phenotype. Taken together, the data suggest that hPSC-derived pSMCs facilitate restoration of urethral sphincter function by direct smooth muscle cell regeneration and by inducing native tissue elastin/collagen III remodeling.
  
  
  
  The present study provides evidence that a pure population of human smooth muscle progenitor cells (pSMCs) derived from human pluripotent stem cells (hPSCs) (human embryonic stem cells and patient induced pluripotent stem cells) restores urethral sphincter function by two mechanisms: modulation of extracellular matrix protein metabolism in vivo and pSMC proliferation and differentiation into smooth muscle cells to regenerate the muscle layer in the lower urinary tract. These findings on the in vivo effects of human pSMCs should aid in optimizing regenerative therapies using human myoblasts.
authors.affiliation: Department of Obstetrics/Gynecology, Stanford University School of Medicine, Stanford, California, USA.|Department of Obstetrics/Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, People's Republic of China.
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Obstetrics/Gynecology, Stanford University School of Medicine, Stanford, California, USA yanwen@stanford.edu.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wen
authors.affiliation: Department of Obstetrics/Gynecology, Stanford University School of Medicine, Stanford, California, USA.|Department of Obstetrics/Gynecology, NanFang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Obstetrics/Gynecology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Department of Obstetrics/Gynecology, Stanford University School of Medicine, Stanford, California, USA.|Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California, USA.
authors.forename: Prachi
authors.initials: P
authors.lastname: Wani
authors.affiliation: Department of Obstetrics/Gynecology, Stanford University School of Medicine, Stanford, California, USA.|Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California, USA.
authors.forename: Morgaine
authors.initials: M
authors.lastname: Green
authors.affiliation: Department of Biomedical Engineering, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Swaminathan
authors.affiliation: Department of Biomedical Engineering, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA.|Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Anand
authors.initials: A
authors.lastname: Ramamurthi
authors.affiliation: Department of Cell Biology and Neuroscience, Montana State University, Bozeman, Montana, USA.|Department of Chemistry and Biochemistry, Montana State University, Bozeman, Montana, USA.
authors.forename: Renee Reijo
authors.initials: RR
authors.lastname: Pera
authors.affiliation: Department of Obstetrics/Gynecology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Bertha
authors.initials: B
authors.lastname: Chen
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002470:Cell Survival; D058948:Cell Tracking; D024061:Collagen Type III / Q000378:metabolism; D004549:Elastin / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D006801:Humans; D008163:Luminescent Measurements; D016513:Mice, SCID; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000637:transplantation; D039904:Pluripotent Stem Cells / Q000166:cytology*; D011923:Rats, Nude; D013234:Stem Cells / Q000166:cytology*; D014521:Urethra / Q000293:injuries* / Q000473:pathology*; D014550:Urinary Incontinence, Stress / Q000628:therapy
chemical_list: D024061:Collagen Type III; D004549:Elastin
keywords: Cell transplantation; Collagen; Elastin; Induced pluripotent stem cells; Myoblasts; Pluripotent stem cells; Regenerative medicine; Smooth muscle; Urinary incontinence