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 A Inverardi, Ricardo Pastori, Juan Dominguez-Bendala

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2455-2468
Number of pages14
JournalCell Reports
Volume22
Issue number9
DOIs
StatePublished - Feb 27 2018

Fingerprint

Bone Morphogenetic Protein 7
Exocrine Pancreas
Bone Morphogenetic Protein Receptors
Pancreatic Ducts
Ducts
Cells
Pancreas
Stem Cells
Purinergic Receptors
Activins
Islets of Langerhans
Phosphotransferases
Population
RNA
Tissue
Glucose
Biomarkers

Keywords

  • ALK3
  • beta cell regeneration
  • human pancreatic progenitor cells
  • islet regeneration
  • PDX1

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

P2RY1/ALK3-Expressing Cells within the Adult Human Exocrine Pancreas Are BMP-7 Expandable and Exhibit Progenitor-like Characteristics. / Qadir, Mirza Muhammad Fahd; Álvarez-Cubela, Silvia; Klein, Dagmar; Lanzoni, Giacomo; García-Santana, Carlos; Montalvo, Abelardo; Pláceres-Uray, Fabiola; Mazza, Emilia Maria Cristina; Ricordi, Camillo; Inverardi, Luca A; Pastori, Ricardo; Dominguez-Bendala, Juan.

In: Cell Reports, Vol. 22, No. 9, 27.02.2018, p. 2455-2468.

Research output: Contribution to journalArticle

Qadir, MMF, Álvarez-Cubela, S, Klein, D, Lanzoni, G, García-Santana, C, Montalvo, A, Pláceres-Uray, F, Mazza, EMC, Ricordi, C, Inverardi, LA, Pastori, R & Dominguez-Bendala, J 2018, 'P2RY1/ALK3-Expressing Cells within the Adult Human Exocrine Pancreas Are BMP-7 Expandable and Exhibit Progenitor-like Characteristics', Cell Reports, vol. 22, no. 9, pp. 2455-2468. https://doi.org/10.1016/j.celrep.2018.02.006
Qadir, Mirza Muhammad Fahd ; Álvarez-Cubela, Silvia ; Klein, Dagmar ; Lanzoni, Giacomo ; García-Santana, Carlos ; Montalvo, Abelardo ; Pláceres-Uray, Fabiola ; Mazza, Emilia Maria Cristina ; Ricordi, Camillo ; Inverardi, Luca A ; Pastori, Ricardo ; Dominguez-Bendala, Juan. / P2RY1/ALK3-Expressing Cells within the Adult Human Exocrine Pancreas Are BMP-7 Expandable and Exhibit Progenitor-like Characteristics. In: Cell Reports. 2018 ; Vol. 22, No. 9. pp. 2455-2468.
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abstract = "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.",
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AU - Klein, Dagmar

AU - Lanzoni, Giacomo

AU - García-Santana, Carlos

AU - Montalvo, Abelardo

AU - Pláceres-Uray, Fabiola

AU - Mazza, Emilia Maria Cristina

AU - Ricordi, Camillo

AU - Inverardi, Luca A

AU - Pastori, Ricardo

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