P2RY1/ALK3-Expressing Cells within the Adult Human Exocrine Pancreas Are BMP-7 Expandable and Exhibit Progenitor-like Characteristics
Mirza Muhammad Fahd Qadir,
Silvia Álvarez-Cubela,
Dagmar Klein,
Giacomo Lanzoni,
Carlos García-Santana,
Abelardo Montalvo,
Fabiola Pláceres-Uray,
Emilia Maria Cristina Mazza,
Camillo Ricordi,
Luca Alessandro Inverardi,
Ricardo Luis Pastori,
Juan Domínguez-Bendala
Affiliations
Mirza Muhammad Fahd Qadir
Diabetes Research Institute, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Department of Cell Biology and Anatomy, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA
Silvia Álvarez-Cubela
Diabetes Research Institute, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA
Dagmar Klein
Diabetes Research Institute, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA
Giacomo Lanzoni
Diabetes Research Institute, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA
Carlos García-Santana
Ophysio, Inc., Miami, FL, USA
Abelardo Montalvo
Diabetes Research Institute, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA
Fabiola Pláceres-Uray
Diabetes Research Institute, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA
Emilia Maria Cristina Mazza
Istituto Clinico Humanitas IRCCS, Milano 20089, Italy
Camillo Ricordi
Diabetes Research Institute, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Department of Microbiology & Immunology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Department of Biomedical Engineering, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA
Luca Alessandro Inverardi
Diabetes Research Institute, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Department of Microbiology & Immunology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Department of Medicine, Division of Metabolism, Endocrinology and Diabetes, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA
Ricardo Luis Pastori
Diabetes Research Institute, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Department of Microbiology & Immunology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Department of Medicine, Division of Metabolism, Endocrinology and Diabetes, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Corresponding author
Juan Domínguez-Bendala
Diabetes Research Institute, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Department of Cell Biology and Anatomy, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Corresponding author
Summary: Treatment of human pancreatic non-endocrine tissue with Bone Morphogenetic Protein 7 (BMP-7) leads to the formation of glucose-responsive β-like cells. Here, we show that BMP-7 acts on extrainsular cells expressing PDX1 and the BMP receptor activin-like kinase 3 (ALK3/BMPR1A). In vitro lineage tracing indicates that ALK3+ cell populations are multipotent. PDX1+/ALK3+ cells are absent from islets but prominently represented in the major pancreatic ducts and pancreatic duct glands. We identified the purinergic receptor P2Y1 (P2RY1) as a surrogate surface marker for PDX1. Sorted P2RY1+/ALK3bright+ cells form BMP-7-expandable colonies characterized by NKX6.1 and PDX1 expression. Unlike the negative fraction controls, these colonies can be differentiated into multiple pancreatic lineages upon BMP-7 withdrawal. RNA-seq further corroborates the progenitor-like nature of P2RY1+/ALK3bright+ cells and their multilineage differentiation potential. Our studies confirm the existence of progenitor cells in the adult human pancreas and suggest a specific anatomical location within the ductal and glandular networks. : Qadir et al. describe and characterize a population of multipotent, BMP-7-responsive progenitor-like cells within the human exocrine pancreas. These cells are characterized by the expression of PDX1 and ALK3, a canonical BMP receptor. Their findings shed new light on potential regenerative pathways in the human pancreas. Keywords: human pancreatic progenitor cells, ALK3, PDX1, islet regeneration, beta cell regeneration