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Purified human hematopoietic stem cells contribute to the generation of cardiomyocytes through cell fusion

Fumihiko Ishikawa^*,¶,1,2, Hideki Shimazu^*,1, Leonard D. Shultz^||, Mitsuhiro Fukata^*, Ryu Nakamura, Bonnie Lyons^||, Kazuya Shimoda^*, Shinji Shimoda^*, Takaaki Kanemaru^*, Kei-ichiro Nakamura, Hiroyuki Ito^*, Yoshikazu Kaji^*, Anthony C.F. Perry and Mine Harada^*

^* Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan;

Second Department of Anatomy, Kurume University School of Medicine, Kurume, Japan;

Zeiss Japan, Tokyo, Japan;

Laboratory of Mammalian Molecular Embryology, RIKEN Center for Developmental Biology, Kobe, Japan;

^|| The Jackson Laboratory, Bar Harbor, Maine; and

^¶ Research Unit for Human Disease Model, RIKEN Center for Allergy and Immunology, Yokohama, Japan

²Correspondence: Kyushu University Graduate School of Medical Sciences, Department of Medicine and Biosystemic Science, 3–1-1 Maidashi, Higashi-ku, Fukuoka 812-8582. E-mail: f_ishika{at}intmed1.med.kyushu-u.ac.jp

ABSTRACT

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/IL2r^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.— Ishikawa, F., Shimazu, H., Shultz, L. D., Fukata, M., Nakamura, R., Lyons, B., Shimoda, K., Shimoda, S., Kanemaru, T., Nakamura, K-i., Ito, H., Kaji, Y., Perry, A. C. F., Harada, M. Purified human hematopoietic stem cells contribute to the generation of cardiomyocytes through cell fusion.

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