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

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/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.

Stem and progenitor cell-mediated tumor selective gene therapy

“…Further, multiple studies found no evidence of bone marrow MSCs or NSC fusion with hepatocytes, pancreatic endocrine cells, endothelial cells or epidermis. [107][108][109][110] While high levels of specific cytokines can induce fusion of MSCs with cardiomyocytes or striated muscle cells, 111,112 it appears that nonembryonic stem cells have little capacity to fuse with cells of a recipient organism. Possibly, fetal or adult stem or progenitor cells will have more utility than embryonic stem cells as delivery vehicles.…”

Current advances in humanized mouse models

“…11 In these mice, extremely high human cell engraftment rates and increases in well-differentiated human multilineage hematopoietic cells from human hematopoietic stem cells (HSCs), as compared with parent immunodeficient mice, were observed. [17][18][19] Humanized mice that retain various human immune cells are often termed human immune system mice 3 or human hematolymphoid system mice. 20 The production of humanized mice that are reconstructed with human cells would facilitate analysis of the underlying mechanisms of human disease pathogenesis.…”

Characteristic Morphology and Distribution of Bone Marrow Derived Cells in the Cornea

“…The GFP(1)Iba1(2) cells observed in the corneal stroma under a fluorescent microscope may represent such cells. On the other hand, it is reported that BM hematopoietic stem cells give rise to cardiomyocytes through cell fusion, not transdifferentiation (Ishikawa et al, 2006). We cannot exclude the possibility that BM-derived GFP(1) cells may fuse with resident corneal keratocytes.…”

“…Nonpurified BM cells harvested from femurs and tibiae of GFP transgenic mice at 8-12 weeks of age, were intravenously injected into wild-type C57BL/6 mice (N 5 6) within 48 hr of birth after 400 cGy irradiation, as previously described (Hisatomi et al, 2003;Ishikawa et al, 2006). The GFP transgenic mice were C57BL/6 mice that transgenically express eGFP driven by the chicken beta actin promoter (Okabe et al, 1997;Ikawa et al, 1998) and purchased from Jackson Laboratory (Bar Harbor, ME).…”