Purified human hematopoietic stem cells contribute to the generation of cardiomyocytes through cell fusion.
To obtain insights into the cardiomyogenic potential of hematopoietic tissue, we intravenously (i.v.) injected purified hematopoietic stem/progenitor cells into newborn recipients that may fully potentiate the developmental plasticity of stem cells. Transplantation of mouse bone marrow (BM) lineage antigen-negative (Lin-) cells resulted in the generation of the cells that displayed cardiomyocyte-specific antigenic profiles and contractile function when transplanted into syngeneic newborn recipients. To clarify the mechanism underlying the cardiomyogenic potential, green fluorescent protein (GFP)-labeled BM Lin-ScaI+ hematopoietic progenitors were transplanted into neonatal mice constitutively expressing cyan fluorescence protein (CFP). Lambda image acquisition and linear unmixing analysis using confocal microscopy successfully separated GFP and CFP, and revealed that donor GFP+ cardiomyocytes coexpressed host-derived CFP. We further reconstituted human hemopoietic- and immune systems in mice by injecting human cord blood (CB)-derived Lin-CD34+CD38- hematopoietic stem cells (HSCs) into neonatal T cell(-)B cell(-)NK cell- immune-deficient NOD/SCID/IL2rgamma(null) mice. Fluoroescence in situ hybridization analysis of recipient cardiac tissues demonstrated that human and murine chromosomes were colocalized in the same cardiomyocytes, indicating that cell fusion occurred between human hematopoietic progeny and mouse cardiomyocytes. These syngeneic- and xenogeneic neonatal transplantations provide compelling evidence that hematopoietic stem/progenitor cells contribute to the postnatal generation of cardiomyocytes through cell fusion, not through transdifferentiation.
Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. f_ishika@intmed1.med.kyushu-u.ac.jp
Fumihiko
F
Ishikawa
Hideki
H
Shimazu
Leonard D
LD
Shultz
Mitsuhiro
M
Fukata
Ryu
R
Nakamura
Bonnie
B
Lyons
Kazuya
K
Shimoda
Shinji
S
Shimoda
Takaaki
T
Kanemaru
Kei-Ichiro
K
Nakamura
Hiroyuki
H
Ito
Yoshikazu
Y
Kaji
Anthony C F
AC
Perry
Mine
M
Harada
D000818:Animals; D002459:Cell Fusion; D002469:Cell Separation; D002478:Cells, Cultured; D002877:Chromosomes, Human; D005786:Gene Expression Regulation; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D032383:Myocytes, Cardiac / Q000166:cytology*; D018123:Receptors, Interleukin / Q000235:genetics
C507941:IL2RG protein, human; C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; D018123:Receptors, Interleukin