Mesenchyme

and circulatory systems. Furthermore, the interactions between mesenchyme and another tissue type, epithelium, help to form nearly every organ in the body

portrayed. The Hertwig brothers established that mesenchyme [5] originates from mesoderm [7] , and they situated this relationship in the broader context of the development of the coelom, a fluid-filled body cavity. Their Die Coelomtheorie also advanced the idea that the three germ layers [11] maintain separate identities and develop distinct tissues and organs, a concept known as germ-layer theory.
In 1888, N. Katschenko suggested that mesenchyme [5] found in the region of the head originated from the neural crest [9] , an ectodermal derivative, effectively expanding the tissue's origins beyond that of a single germ layer. Five years later, Harvard Medical School [13] doctoral student Julia Platt, in Cambridge, Massachusetts, provided evidence based on her studies of Necturus maculosus embryos, a type of aquatic salamander [16] , that the mesenchyme [5] that developed into the skeletal elements of the branchial arches derived from ectoderm [8] . Platt's 1893 publication, "Ectodermic Origin of the Cartilages of the Head," and her conclusions about the ectodermal origins of mesenchyme [5] in the head region, and thus skeletal and cartilaginous tissues of the skull, went against the entrenched germlayer theory and the mesodermal origins of mesenchyme [5] advocated by the Hertwig brothers in their 1881 Die Coelomtheorie. Platt's findings were rejected by many established embryologists who upheld the theory of integrity of the germ layers [11] .
In the years following Platt's publication, several other embryologists identified ectodermal origins for mesenchyme [5] and its derivative skeletal elements in the head region of fish [17] and birds [18] . It was not until nearly thirty years after Platt's initial publication that independent studies demonstrated a major ectodermal contribution to mesenchyme [5] . In 1921, while investigating the limits of neural crest [9] in the formation of cerebral ganglia in Urodeles, commonly known as salamanders [19] , Francis Landacre at the Ohio State University in Columbus, Ohio, showed the ectodermal origin of cranial mesenchyme [5] . Landacre's work was followed by other studies which further concluded an ectodermal component of mesenchyme [5] . The idea that mesenchyme [5] in the cranial region derived from neural crest [9] was finally abrogated in the 1940s by the independent research of embryologists Sven Hörstadius at Uppsala University in Uppsala, Sweden, and Gavin de Beer at the University College [20] in London, England.
Soon after the debate over ectodermal mesenchyme [5] ended, research on the role of mesenchyme [5] during development erupted. By the 1960s, embryologists realized that mesenchyme [5] , in combination with epithelium [6] , played an essential role in the morphogenesis of many organs during embryonic and fetal development. Epithelio-mesenchymal interactions form nearly every organ of the body, from hair and sweat glands to the digestive tract, kidneys, and teeth.
In 1969, Edward Kollar and Grace Baird from the University of Chicago [21] in Chicago, Illinois, designed a series of experiments to understand how mesenchyme [5] and epithelium [6] work together when cells differentiate, and how the two tissues combine to make embryonic structures. Their research drew on a long history of investigating tissue interactions during morphogenesis, and especially on the 1954 work of John Cairn at the University of Texas in Austin, Texas, and John Saunders, at Marquette University [22] in Milwaukee, Wisconsin. Cairn and Saunders recognized that mesoderm [7] holds the inductive stimulus within interactions between mesoderm [7] and epithelium [6] . Using tooth development as a model system, Kollar and Baird provided evidence that mesenchyme [5] drives both induction [23] and differentiation [24] during epithelio-mesenchymal interactions, and is thus the tissue that confers structural specificity during these interactions, or determines what structure will form. Kollar  Shortly before Kollar and Baird published their account of epithelio-mesenchymal interactions, Alexander Friedenstein discovered mesenchymal stem cells [10] in mice [25] (Mus musculus). In publications from 1966 through 1987, Friedenstein, in conjunction with his peers at the University of Moscow in Moscow, Russia, provided evidence from transplantation experiments that stem cells [10] taken from bone marrow can differentiate into mesenchymal tissues, such as fat, bone, and cartilage. These cells came to be known as mesenchymal stem cells [10] , and have subsequently been found in blood, cartilaginous, skeletal, and fatty tissues. Mesenchymal stem cells [10] provide a reservoir of reserve cells that the body can use for normal or pathological tissue regeneration and repair. The abilities of mesenchymal stem cells [10] to differentiate into different tissues, known as cell potency, has been a cause of debate in recent years, leading researchers to question whether these cells are truly multipotent, and can give rise to multiple cells types. The potential multipotency [26] of mesenchymal stem cells [10] , in conjunction with their presence in adult organisms, has made them an attractive alternative to embryonic stem cells [27] for research on tissue regeneration.
Current research on mesenchyme [5] spreads across many biological fields. The focus of mesenchyme [5] research, however, divides between two general interests: the role and expression of mesenchyme [5] -specific genes [28] during development, including pathological processes, and the locations and capabilities of mesenchymal stem cells [10] . While some still investigate mesenchyme [5] at the tissue level, the two current focuses reflect a trend towards the analysis and understanding of molecular-level mechanisms by which mesenchyme [5] functions during development. Beginning with the definition by the Hertwig brothers, mesenchyme [5] research has moved from anatomical investigations in developing embryos, to cellular contributions for organ formation and tissue level interactions, and now to the genetic mechanisms of development and tissue repair.
There is historical continuity within mesenchyme [5] research, but there remain vestiges of the controversy that surrounded this tissue in the late nineteenth century. In her 1893 article in which she introduced the biological community to the ectodermal origins of mesenchyme [5] in the head region, Julia Platt also suggested a change in terminology. Mesenchyme of ectodermal origins she specified by the term mesectoderm, while mesodermal mesenchyme [5] she called mesendoderm. The medical community, especially pathologists, still employs this distinction between mesenchymal sources, only referring to a tissue as mesenchyme [5] if it is derived from mesoderm [7] . Pathologists maintain the distinction because the mesenchymal source determines the type and behavior of a disease. Meanwhile, developmental biologists tend to recognize mesenchyme [5] by a single name, regardless of source.
The study of mesenchyme [5] has a long history, from mesenchyme [5] 's recognition within the framework of germ-layer theory, to controversy about mesenchyme [5] 's origins, to uncovering mesenchyme [5] 's roles in morphogenesis and its capacity to produce stem cells [10] . This history is in part due to the fact that mesenchyme [5] is crucial for embryonic growth and development, as well as maintenance of connective tissues in adulthood. The loose nature of cells within mesenchyme [5] allows the tissue to move and to be molded. During embryogenesis [29] , mesenchyme [5] gives rise to the body's connective tissues, from cartilage and bone to fat, muscle, and the circulatory system. Meanwhile, nearly every organ forms through epithelio-mesenchymal interactions, in which mesenchyme [5] provides both the inductive stimulus and determines the path of differentiation [24] . Although little mesenchyme [5] remains in the body during adulthood, the final remnants of this tissue, mesenchymal stem cells [10] , allow connective tissues to repair and regenerate.