Adult muscle-derived stem cells engraft and differentiate into insulin-expressing cells in pancreatic islets of diabetic mice

Violeta Mitutsova (1) , Wendy Wai Yeng Yeo (1, 2) , Romain Davaze (1) , Céline Franckhauser (1) , El-Habib Hani (1) , Syahril Abdullah (2) , Patrice Mollard (3) , Marie Schaeffer (3) , Anne Fernandez (1) , Ned J.C. Lamb (1)

1 IGH - Institut de génétique humaine
2 Universiti Putra Malaysia
3 IGF - Institut de Génomique Fonctionnelle

Background : Pancreatic beta cells are unique effectors in the control of glucose homeostasis and their deficiencyresults in impaired insulin production leading to severe diabetic diseases. Here, we investigated the potential of apopulation of nonadherent muscle-derived stem cells (MDSC) from adult mouse muscle to differentiate in vitro intobeta cells when transplanted as undifferentiated stem cells in vivo to compensate for beta-cell deficiency. Results : In vitro, cultured MDSC spontaneously differentiated into insulin-expressing islet-like cell clusters asrevealed using MDSC from transgenic mice expressing GFP or mCherry under the control of an insulin promoter.Differentiated clusters of beta-like cells co-expressed insulin with the transcription factors Pdx1, Nkx2.2, Nkx6.1, andMafA, and secreted significant levels of insulin in response to glucose challenges. In vivo, undifferentiated MDSCinjected into streptozotocin (STZ)-treated mice engrafted within 48 h specifically to damaged pancreatic islets andwere shown to differentiate and express insulin 10–12 days after injection. In addition, injection of MDSC intohyperglycemic diabetic mice reduced their blood glucose levels for 2–4 weeks. Conclusion : These data show that MDSC are capable of differentiating into mature pancreatic beta islet-like cells,not only upon culture in vitro, but also in vivo after systemic injection in STZ-induced diabetic mouse models.Being nonteratogenic, MDSC can be used directly by systemic injection, and this potential reveals a promisingalternative avenue in stem cell-based treatment of beta-cell deficiencies.

Mots clés: Muscle stem cells; Beta-cell differentiation; Insulin secretion; Pancreatic islets

Domaines: Génétique; Organisation et fonctions cellulaires [q-bio.SC]

Violeta Mitutsova, Wendy Wai Yeng Yeo, Romain Davaze, Céline Franckhauser, El-Habib Hani, et al.. Adult muscle-derived stem cells engraft and differentiate into insulin-expressing cells in pancreatic islets of diabetic mice. Stem Cell Research and Therapy, 2017, 8, pp.86. ⟨10.1186/s13287-017-0539-9⟩. ⟨hal-01511492⟩