title: Microfluidic single-cell analysis shows that porcine induced pluripotent stem cell-derived endothelial cells improve myocardial function by paracrine activation.
abstract: BACKGROUND
  Induced pluripotent stem cells (iPSCs) hold great promise for the development of patient-specific therapies for cardiovascular disease. However, clinical translation will require preclinical optimization and validation of large-animal iPSC models.
  
  
  OBJECTIVE
  To successfully derive endothelial cells from porcine iPSCs and demonstrate their potential utility for the treatment of myocardial ischemia.
  
  
  RESULTS
  Porcine adipose stromal cells were reprogrammed to generate porcine iPSCs (piPSCs). Immunohistochemistry, quantitative PCR, microarray hybridization, and angiogenic assays confirmed that piPSC-derived endothelial cells (piPSC-ECs) shared similar morphological and functional properties as endothelial cells isolated from the autologous pig aorta. To demonstrate their therapeutic potential, piPSC-ECs were transplanted into mice with myocardial infarction. Compared with control, animals transplanted with piPSC-ECs showed significant functional improvement measured by echocardiography (fractional shortening at week 4: 27.2±1.3% versus 22.3±1.1%; P<0.001) and MRI (ejection fraction at week 4: 45.8±1.3% versus 42.3±0.9%; P<0.05). Quantitative protein assays and microfluidic single-cell PCR profiling showed that piPSC-ECs released proangiogenic and antiapoptotic factors in the ischemic microenvironment, which promoted neovascularization and cardiomyocyte survival, respectively. Release of paracrine factors varied significantly among subpopulations of transplanted cells, suggesting that transplantation of specific cell populations may result in greater functional recovery.
  
  
  CONCLUSIONS
  In summary, this is the first study to successfully differentiate piPSCs-ECs from piPSCs and demonstrate that transplantation of piPSC-ECs improved cardiac function after myocardial infarction via paracrine activation. Further development of these large animal iPSC models will yield significant insights into their therapeutic potential and accelerate the clinical translation of autologous iPSC-based therapy.
authors: Department of Medicine, Division of Cardiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Mingxia
authors: M
authors: Gu
authors: Patricia K
authors: PK
authors: Nguyen
authors: Andrew S
authors: AS
authors: Lee
authors: Dan
authors: D
authors: Xu
authors: Shijun
authors: S
authors: Hu
authors: Jordan R
authors: JR
authors: Plews
authors: Leng
authors: L
authors: Han
authors: Bruno C
authors: BC
authors: Huber
authors: Won Hee
authors: WH
authors: Lee
authors: Yongquan
authors: Y
authors: Gong
authors: Patricia E
authors: PE
authors: de Almeida
authors: Jennifer
authors: J
authors: Lyons
authors: Fumi
authors: F
authors: Ikeno
authors: Cholawat
authors: C
authors: Pacharinsak
authors: Andrew J
authors: AJ
authors: Connolly
authors: Sanjiv S
authors: SS
authors: Gambhir
authors: Robert C
authors: RC
authors: Robbins
authors: Michael T
authors: MT
authors: Longaker
authors: Joseph C
authors: JC
authors: Wu
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D017690:Cell Transplantation; D002478:Cells, Cultured; D004452:Echocardiography; D004730:Endothelium, Vascular / Q000166:cytology* / Q000502:physiology / Q000637:transplantation*; D005260:Female; D006321:Heart / Q000503:physiopathology*; D008279:Magnetic Resonance Imaging; D051379:Mice; D016513:Mice, SCID; D046210:Microfluidic Analytical Techniques; D023421:Models, Animal; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000473:pathology; D018919:Neovascularization, Physiologic; D019899:Paracrine Communication / Q000502:physiology*; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000502:physiology; D013552:Swine; D013556:Swine, Miniature