Human induced pluripotent stem cells can reach complete terminal maturation: in vivo and in vitro evidence in the erythropoietic differentiation model.
BACKGROUND
Human induced pluripotent stem cells offer perspectives for cell therapy and research models for diseases. We applied this approach to the normal and pathological erythroid differentiation model by establishing induced pluripotent stem cells from normal and homozygous sickle cell disease donors.


METHODS
We addressed the question as to whether these cells can reach complete erythroid terminal maturation notably with a complete switch from fetal to adult hemoglobin. Sickle cell disease induced pluripotent stem cells were differentiated in vitro into red blood cells and characterized for their terminal maturation in terms of hemoglobin content, oxygen transport capacity, deformability, sickling and adherence. Nucleated erythroblast populations generated from normal and pathological induced pluripotent stem cells were then injected into non-obese diabetic severe combined immunodeficiency mice to follow the in vivo hemoglobin maturation.


RESULTS
We observed that in vitro erythroid differentiation results in predominance of fetal hemoglobin which rescues the functionality of red blood cells in the pathological model of sickle cell disease. We observed, in vivo, the switch from fetal to adult hemoglobin after infusion of nucleated erythroid precursors derived from either normal or pathological induced pluripotent stem cells into mice.


CONCLUSIONS
These results demonstrate that human induced pluripotent stem cells: i) can achieve complete terminal erythroid maturation, in vitro in terms of nucleus expulsion and in vivo in terms of hemoglobin maturation; and ii) open the way to generation of functionally corrected red blood cells from sickle cell disease induced pluripotent stem cells, without any genetic modification or drug treatment.
UPMC Univ Paris 06, UMR_S938 CDR Saint-Antoine, Prolifération et Différentiation des Cellules Souches, Paris, France.
Ladan
L
Kobari
Frank
F
Yates
Noufissa
N
Oudrhiri
Alain
A
Francina
Laurent
L
Kiger
Christelle
C
Mazurier
Shaghayegh
S
Rouzbeh
Wassim
W
El-Nemer
Nicolas
N
Hebert
Marie-Catherine
MC
Giarratana
Sabine
S
François
Alain
A
Chapel
Hélène
H
Lapillonne
Dominique
D
Luton
Annelise
A
Bennaceur-Griscelli
Luc
L
Douay
D000328:Adult; D000653:Amniotic Fluid / Q000737:chemistry; D000755:Anemia, Sickle Cell / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D002448:Cell Adhesion; D002454:Cell Differentiation; D002478:Cells, Cultured; D004912:Erythrocytes / Q000378:metabolism / Q000473:pathology*; D004920:Erythropoiesis / Q000502:physiology*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005434:Flow Cytometry; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010100:Oxygen / Q000378:metabolism
D006454:Hemoglobins; D010100:Oxygen