Milk Synthesis

R. Michael Akers

Virginia Polytechnic Institute and State University, Blacksburg, Virginia, U.S.A.

INTRODUCTION

Copious milk secretion begins shortly after parturition and requires: 1) the prepartum proliferation of alveolar epithelial cells; 2) biochemical and structural differentiation of these cells; and 3) synthesis and secretion of milk constituents. Except for bottle-fed humans and milk replacer-fed dairy calves, the success of reproduction does not end with the birth of healthy offspring. Rather, suckling of the neonate determines survival.

Milk synthesis and secretion are biological marvel and hallmark of mammals. Milk contains proteins, carbohydrates, and fats suspended in an aqueous medium. The purposes of this article are to: 1) provide an overview of the dramatic, acute changes in secretory cell structure and function as the gland prepares for onset of copious milk secretion, and 2) describe the activity and function of the secretory cells to promote milk synthesis and secretion.

PROPERTIES OF MAMMARY SECRETIONS

The mammary gland is an unusual exocrine gland. Its product is a complex mixture, which depends on apocrine and meocrine modes of cellular secretion. Milk is stored within the lumen of the alveoli and ductular system until it is removed by the milking machine or the suckling offspring. Interestingly, suckling intervals vary widely between mammals, ranging from minutes to hours in cattle, to once daily in rabbits, to once every two days in tree shrews, or only once a week in some seals. There are species-specific changes in milk composition with stage of lactation, but milk composition is generally only moderately affected by environmental or nutritional changes.[1] Function of the mammary gland during established lactation is closely linked with a number of hormones, growth factors, and local tissue regulators, but it is difficult to ascribe a specific transport activity to a particular molecule or to determine whether effects are direct or indirect.[2-5]

Requirements for high levels of milk production are staggering. In the dairy cow, the energy requirements for milk production can approach 80% of net energy of intake. Lactose production may require 85% of available glucose. Approximately one-third of the milk produced during the first month or more of lactation is energetically accounted for by mobilization of endogenous nutrient reserves. Finely tuned coordinated interactions between all the major physiological systems are essential.

OVERVIEW OF MAMMARY STRUCTURE

During the second half of gestation, alveolar formation predominates mammogenesis as new alveoli appear and existing alveoli increase in size. Connected via a terminal duct to progressively larger ducts and ultimately to the teat or nipple, it is the epithelial cells of the many alveoli that synthesize and secrete milk. Once initiated, secreted milk is stored in the spaces of the hollow alveoli and ducts between milking and suckling episodes (Fig. 1). There is also storage of milk in the gland and teat cisterns of those animals where mammary glands are arranged into an udder (ruminants).[1]

SECRETORY CELL DIFFERENTIATION

Biochemical differentiation of the secretory cells is critical, but the alveolar cells must also acquire the structural machinery needed to synthesize, package, and secrete milk constituents. When they first appear, the cells exhibit few of the needed organelles (Fig. 2). They are characterized by a sparse cytoplasm with few polyribo-somes or free ribosomes, limited rough endoplasmic reticulum, rudimentary Golgi, some isolated mitochondria, and occasional widely dispersed vesicles. Soon after the alveolar structures appear, alveolar and ductal spaces accumulate fluid and progressively increase concentrations of serum-derived proteins. Accumulated secretions result in formation of immunoglobulin-rich colostrums, which depending on the species may be essential for the survival of the offspring. As parturition approaches, the cells undergo a dramatic structural transformation. Cell nuclei become rounded and displaced to the basal area of the cell. Lateral and basal regions of the cell become filled with arrays of rough endoplasmic reticulum and small lipid droplets. The apical area becomes populated with swollen arrays of Golgi membranes,

Fig. 1 Developing mammary tissue. The upper panel shows a microscopic view of a section of mammary parenchymal tissue from a nonlactating heifer about mid gestation. Developing alveoli are evident in clusters of epithelial tissue surrounded by connective tissue (bar indicates 25 mm). The lower panel illustrates mammary tissue from a lactating cow. Notice how the entire parenchymal tissue area is occupied by closely aligned alveoli. Several alveoli cut in cross section are illustrated. Lighter stained areas are alveolar lumena. Secretory cells form a single layer around the periphery of each alveolus. Because of accumulation of secretions within the lumenal spaces, alveoli are closely packed together with little apparent stomal or vascular tissue (bar indicates 10 mm). (View this art in color at www. dekker.com.)

Fig. 1 Developing mammary tissue. The upper panel shows a microscopic view of a section of mammary parenchymal tissue from a nonlactating heifer about mid gestation. Developing alveoli are evident in clusters of epithelial tissue surrounded by connective tissue (bar indicates 25 mm). The lower panel illustrates mammary tissue from a lactating cow. Notice how the entire parenchymal tissue area is occupied by closely aligned alveoli. Several alveoli cut in cross section are illustrated. Lighter stained areas are alveolar lumena. Secretory cells form a single layer around the periphery of each alveolus. Because of accumulation of secretions within the lumenal spaces, alveoli are closely packed together with little apparent stomal or vascular tissue (bar indicates 10 mm). (View this art in color at www. dekker.com.)

developing secretory vesicles and small lipid droplets. Even in the light microscope, these changes are evident (Fig. 2). A lacy appearance highlights the apical region of the cell because of the abundance of secretory vesicles, in contrast to the darkly stained basal lateral cytoplasm. The fully differentiated cell becomes polarized with the basolateral area devoted to the uptake of precursors and synthesis of proteins and lipids and the apical cytoplasm, with now abundant Golgi, devoted to posttranslational modification of proteins and packaging of proteins and lactose for secretion from the cell.

Five routes of secretion across the mammary epithelium have been described: 1) membrane route; 2) Golgi route; 3) milk fat route; 4) transcytosis; and 5) the paracellular route. The membrane route refers to interstitial fluid derived substances that cross the basolateral membrane, traverse the cell, and pass across the apical membrane into milk. Examples are water, urea, glucose, and some ions. To utilize the Golgi route, products are synthesized, sequestered, or packaged into secretory vesicles that bud from the stacks of Golgi membranes. These vesicles, either individually or in chains, fuse with the apical plasma membrane to release their contents to become part of milk. Examples include lactose, caseins, whey proteins, citrate, and calcium. The milk fat route refers to substances that become entrained with the budding lipid droplets as they are released from the apical cell surface to become part of milk. Actually, as the fat droplets are secreted, bits of cytoplasm can become engulfed by plasma membrane and secreted from the cell. They are especially common in the milk of goats. In transcytosis, vesicles derived from the basolateral membrane (pinocytosis or endocytosis) are transported in membrane-bound vesicles for release at the apical membrane. Finally, in the paracellular route there is

Fig. 2 Mammary tissue from a cow about two weeks prepartum is illustrated in the upper panel. Secretory cells from three alveoli are shown. At this point the cells are very poorly differentiated with little indication of secretory activity. The lower panel illustrates portions of two alveoli about one week postpartum. The secretory cells are well differentiated, basal areas of the cells are darkly stained, and apical regions have a distinct lacy appearance because of the presence of numerous secretory vesicles and lipid droplets (bars indicate 10 mm). (View this art in color at www.dekker.com.)

Fig. 2 Mammary tissue from a cow about two weeks prepartum is illustrated in the upper panel. Secretory cells from three alveoli are shown. At this point the cells are very poorly differentiated with little indication of secretory activity. The lower panel illustrates portions of two alveoli about one week postpartum. The secretory cells are well differentiated, basal areas of the cells are darkly stained, and apical regions have a distinct lacy appearance because of the presence of numerous secretory vesicles and lipid droplets (bars indicate 10 mm). (View this art in color at www.dekker.com.)

direct passage for materials in the interstitial fluids between the epithelial cells and into milk. Except in situations of disease, i.e., mastitis or failure of frequent milk removal, the paracellular route is likely of minimal importance during established lactation.[1]

Production of milk requires close coordination between biochemical pathways to supply synthesis intermediates and secretory pathways for secretion. To illustrate, the disaccharide lactose is the predominate sugar in milk. The enzyme complex necessary for lactose synthesis, membrane-bound galactosyltransferase and the whey protein a-lactalbumin, combines in the Golgi apparatus to form lactose synthetase, which serves to combine glucose and galactose and thereby form lactose. Activation of the a-lactalbumin gene occurs near parturition and heralds the onset of lactogenesis. Moreover, continuing synthesis of lactose is essential to maintain milk volume and composition. This is because lactose becomes trapped in secretory vesicles and water is osmotically drawn into the vesicles. Because the plasma membranes of the secretory and ductular cells are also impermeable to lactose, the osmolarity of the secretory vesicles is maintained in secreted milk and water remains within the lumens of the alveoli and ducts. It is generally accepted that some minimal level of lactose production is likely essential to maintain the relative fluidity of milk for efficient milk removal either by the sucking young or the milking machine. This is perhaps best illustrated by recent data for transgenic mice in which prevention of a-lactalbumin synthesis essentially prevented lactation, because sucking mice failed to survive despite the presence of milk proteins and fat in the alveolar spaces of mammary tissue of lactating mothers.

CONTROL OF MILK SYNTHESIS

As confirmed in numerous species, classical mammary explant culture studies demonstrated that the major positive regulators of differentiation of the secretory cells are glucocorticoids and prolactin.[4] Recent data support the idea that insulin-mediated effects on mammary cells in culture may actually represent effects more appropriately ascribed to the insulin-like growth factors (IGF-I and IGF-II). This is because mammary epithelial cells have specific IGF-I receptors, and insulin (especially at higher concentrations typical of culture experiments) is likely to bind to the IGF-I receptor. In general terms, glucocorticoids are most closely associated with development of rough endoplasmic reticulum and prolactin with maturation of the Golgi apparatus and appearance of secretory vesicles.[4]

Molecular techniques applied to mammary gland biology have served to solidify the idea that prolactin and glucocorticoids are primary stimulators of mammary cell differentiation. For example, both prolactin and glucocorticoid response elements are found within the promoter regions of the genes for several mammary-specific milk proteins. Similarly, induction of both mRNA and specific milk proteins in response to the addition of prolactin or glucocorticoids in isolated mammary epithelial cells indicate the importance of these hormones in lactogenesis.[2,3]

CONCLUSION

Lactogenesis the onset of copious milk synthesis and secretion that is initiated near the time of parturition is stimulated by the positive actions of prolactin and glucocorticoids and the removal of the negative effects of progesterone. These hormonal changes promote both biochemical and structural differentiation of the alveolar epithelial cells that are required for synthesis, cellular packaging, and secretion of milk components.

REFERENCES

1. Akers, R.M. Lactation and the Mammary Gland; Iowa State Press: USA, 2003.

2. Capuco, A.V.; Akers, R.M. Galactopoiesis, Effects of Hormones and Growth Factors. In Encyclopedia of Dairy Science; Academic Press: New York, 2002; Vol 3, 1452 1458.

3. Capuco, A.V.; Akers, R.M. Galactopoiesis, Effect of bST Treatment. In Encyclopedia of Dairy Science; Academic Press: New York, 2002; Vol 3, 1458 1464.

4. Tucker, H.A. Lactation and Its Hormonal Control. In The Physiology of Reproduction, 2nd Ed.; Knobil, E., Neill, J.D., Eds.; Raven Press Ltd.: New York, 1994; 1065 1098. Chapter 57.

5. Akers, R.M. Lactation. In Encyclopedia of Agricultural Science; Academic Press: New York, 1994; Vol 2, 635 643.

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