Normal mammalian muscle differentiation and gene control of isocitrate dehydrogenase synthesis.

Abstract

A new kind of laboratory mammal, the allophenic mouse, has been described by MinltZ.1' 2 These animals are artificial creations, since they are formed by aggregating cleavage-stage blastomeres in vitro from embryos of different genotypes, and the composites are then transferred to an "incubator" mother for further development. Despite their strange history, hundreds of such mosaic embryos have gone oIl to become healthy and long-lived adults. The mice are called allophenic because they display an orderly arrangement of two concurrent, allelically alternative cellular phenotypes, or allophenes.2 Many biological problems are open to examination in these individuals, inasmuch as their component genotypes can be chosen without restriction. In the present report, a question is raised which could have many implications for development or disease: Do cells fuse in the organism?The possibility that fusion between somatic cells might be made to occur experimentally was first suggested by Schultz3 and by Lederberg.4 It was soon taken up with methods chiefly applicable to cell cultures, in a series of imaginative in vitro experiments.5-8 The allophenic mouse provides an ideal way to obtain an unambiguous answer to the question of spontaneous cell fusion in vivo, for any normal tissue or for malignant ones.This study will be primarily concerned with skeletal muscle because, unlike most of the other tissues in the body, its cells are multinucleated rather than uninucleated. Definitive muscle arises from narrow tubules, or myotubes, in which many nuclei are arranged in approximately single file within a common cytoplasm. Myotubes in turn, are derived from uninucleated cells, the spindle-shaped myoblasts. The developmental transition from a uninucleated to a multinucleated state might, hypothetically, occur either by repeated nuclear division without cytoplasmic cleavage or by fusion of myoblasts. The debate as to which of these is in fact the normal mechanism has been sustained for well over half a century. There have been many observations on growth and regeneration of muscle in vivo, but the chief arena in which hypotheses of myogenesis have been tested experimentally has been the in vitro one. Here myoblasts of mammalian and of avian origin have been found to form myotubes by fusion.9-13 The query which has persisted is whether this behavior reflects the situation in the organism, or is an in vitro peculiarity.Within an allophenic mouse, if some cells were to fuse, multinucleated heterokaryons could be formed. In the event that the two strains of cells were each homozygous for a different allele at an appropriate enzyme locus, hybrid enzyme molecules might be synthesized in the heterokaryons. Thus occurrence of cell fusion could be detected by simple biochemical means. An example of an enzyme favorable for this purpose is the nicotinamide-adenine dinucleotide phosphate (NADP)-dependent isocitrate dehydrogenase found in the supernatant fraction of homogenates of many mouse tissues, including muscle. The autosomal isocitrate ...

Clonally expanded novel multipotent stem cells from human bone marrow regenerate myocardium after myocardial infarction

“…Both in vitro (25) and in vivo (26, 28) experiments using ES cells and/or BM-derived stem cells showed that cell fusion is responsible for a certain percentage of phenotypic changes observed following stem cell transplantation. Cell fusion occurs in normal mammalian development during the formation of osteoclasts (36) and myoblasts (37) or during tumor progression (38). Recent in vivo studies suggest that hepatocytes derived from cell fusion of HSCs and host hepatocytes can correct underlying metabolic disorders and that fused cells can undergo reduction division (26).…”

The therapeutic effect of bone marrow–derived liver cells in the phenotypic correction of murine hemophilia A

“…49,50 Cell fusion occurs during normal mammalian development. 51,52 In adult mammals, cell fusion may be associated with chromosomal abnormalities that can lead to oncogenic transformations. 53 Thus, it is crucial…”

Satellite cells are essential for skeletal muscle regeneration: the cell on the edge returns centre stage

“…1A). Myofibres are multinucleated, often containing hundreds of myonuclei, and are formed by the fusion of many myoblasts during embryonic and foetal development (Mintz and Baker, 1967).…”