Abstract
BackgroundIn the bovine species milk production is well known to correlate with mammary tissue mass. However, most advances in optimizing milk production relied on improvements of breeding and husbandry practices. A better understanding of the cells that generate bovine mammary tissue could facilitate important advances in milk production and have global economic impact. With this possibility in mind, we show that a mammary stem cell population can be functionally identified and isolated from the bovine mammary gland. We also demonstrate that this stem cell population may be a promising target for manipulating the composition of cow's milk using gene transfer.Methods and FindingsWe show that the in vitro colony-forming cell assay for detecting normal primitive bipotent and lineage-restricted human mammary clonogenic progenitors are applicable to bovine mammary cells. Similarly, the ability of normal human mammary stem cells to regenerate functional bilayered structures in collagen gels placed under the kidney capsule of immunodeficient mice is shared by a subset of bovine mammary cells that lack aldehyde dehydrogenase activity. We also find that this activity is a distinguishing feature of luminal-restricted bovine progenitors. The regenerated structures recapitulate the organization of bovine mammary tissue, and milk could be readily detected in these structures when they were assessed by immunohistochemical analysis. Transplantation of the bovine cells transduced with a lentivirus encoding human β-CASEIN led to expression of the transgene and secretion of the product by their progeny regenerated in vivo.ConclusionsThese findings point to a common developmental hierarchy shared by human and bovine mammary glands, providing strong evidence of common mechanisms regulating the maintenance and differentiation of mammary stem cells from both species. These results highlight the potential of novel engineering and transplant strategies for a variety of commercial applications including the production of modified milk components for human consumption.
Highlights
Normal mammalian mammary tissue is a bilayered system organized into alveolar structures connected by a common ductal system
These findings point to a common developmental hierarchy shared by human and bovine mammary glands, providing strong evidence of common mechanisms regulating the maintenance and differentiation of mammary stem cells from both species
Identification of bovine mammary progenitor cells We first sought to determine whether the methods developed for quantifying human mammary cells with in vitro clonogenic potential would enable the detection of analogous populations in bovine mammary tissue
Summary
Normal mammalian mammary tissue is a bilayered system organized into alveolar structures connected by a common ductal system. Detection of human mammary stem cells has taken advantage of the creation of genetically immunodeficient strains of mice that lack a normal complement of natural killer cells as well as B and T cells [9] to enable in vivo transplant assay strategy to be developed. These make use of a fibroblast-enhanced mammary fat pad or gel implants containing fibroblasts as well as the test cells to create a suitable growth-promoting environment [4,10,11]. We demonstrate that this stem cell population may be a promising target for manipulating the composition of cow’s milk using gene transfer
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