NDC mechanobiological model #1: hydrostatic stretching and compression acts as a mechanical Feedback Inhibitor of Lactation, downregulating breastmilk secretion
The NDC mechanobiological models of human mammary gland function draw on findings in the new field of mechanobiology
The NDC mechanobiological model of human mammary gland function in lactation has four elements, each with specific clinical implications:
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The mechanobiological model of breast inflammation, here
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The mechanobiological model of nipple pain and damage, here
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The mechanobiological model of upregulation of milk secretion, here
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The hydrostatic compression Feedback Inhibitor of Lactation model of downregulation of milk secretion, discussed in this article.
The hydrostatic compression Feedback Inhibitor of Lactation model
The hypothesis that hydrostatic stretching and compression acts as the dominant Feedback Inhibitor of Lactation
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Is a clinical interpretation of the work emerging out of the field of mechanobiology, discussed here and here
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Builds on early work in domestic mammalian species which posited that mechanical forces downregulated milk production. You can find a discussion of why this work has been subsequently and inappropriately ignored here and here.
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Draws on three important recent research studies.
There are two components to this hypothesis.
1. Hydrostatic compression causes stretching of lactocytes and their tight junctions and sometimes apoptosis
The mechanical effects of stretching of the lactocyte cell membrane are not yet clearly elucidated. It is not known for certain if mechanical forces exert an immediate downregulatory effect upon lactocyte cell membrane’s capacity to exocytose protein and lactose in Golgi-derived secretory vesicles or upon cell membrane permeability to water and ions. However, this seems likely.
Tight junction strain triggers chemical signals, such as cytokines, chemokines, and adhesion molecules, which warn the host immune system of early cell and tissue damage, recruiting local hyperemia and increased leukocytes. Sodium, chloride and albumin from the plasma may pass directly through the tight junctions as they open up under mechanical strain, increasing intra-alveolar volume.
Increasing milk accumulation exerts shearing or compression forces on tight junctions, which stretch and may finally break under severe mechanical stress, so that the alveolus and its basement membrane rupture. This precipitates a dynamic wound-healing inflammatory response in the stroma and milk, proteolytic degradation of the alveolar basement membrane, and lactocyte apoptosis. Immune cells and perhaps more importantly, other mammary epithelial cells, phagocytose debris from these small subclinical areas of involution. Lactocytes are replaced with adipocytes as tissue is repaired and remodelled.
The healthy lactating mammary gland is a proinflammatory environment. Lactation and the body’s inflammatory response share many common mechanisms. Applying the mechanobiological theory of breast inflammation in lactation, normal wound-healing processes occur microscopically throughout the course of a healthy and successful lactation in response to intermittent excessively high intra-alveolar and intra-ductal pressures, without the development of pathological signs and symptoms which present clinically.
Approaching six months post-birth, an infant begins to ingest solids. At this time, maternal milk secretion decreases through the same mechanism of elevated intraluminal pressures, tight junction rupture, alveolar collapse and lactocyte death.
Complete cessation of breastfeeding, whenever this occurs, triggers one of the largest cascades of programmed cell death to occur in mammals: 80-90% of remaining lactocytes switch from milk secretion to apoptosis. During complete weaning, breast stroma is characterised by a heightened inflammatory or wound-healing environment, including activation of macrophages, lymphangiogenesis, and fibroblasts for tissue repair and remodelling.
The post-weaning cascade of inflammatory activity and cell death peaks two weeks after the last breastfeed and is largely resolved by 4 weeks after the last breastfeed.
When more milk is removed, there is a decreased inhibitory effect of hydrostatic or mechanical pressures, which allows optimal secretion of milk from the lactocytes. When milk builds up, hydrostatic pressure resulting in both stretching of the lactocytes and tension on the tight junctions are hypothesised to turn down lactocyte milk secretion.
I recommend avoiding the term 'milk stasis' because milk secretion is never in stasis! The term milk stasis has led to mistaken beliefs that you can physically ‘move’ or ‘shake up’ the milk with vibrators, massage and toothbrushes, or that you can ‘thin’ your milk by taking lecithin.
2. Hydrostatic pressure causes stretching of stem cells and their tight junctions which inhibits stem cell differentiation and proliferation
It is known that high hydrostatic pressures cause lactocytes to change shape, from apical to elongated and rectangular, with increasing strain placed upon the tight junctions between them.
The resultant mechanosensing and mechanotransduction responses trigger multiple chemical signals and calcium changes both intracellularly and in the cell membrane. Calcium helps control the genetic regulation of protein expression.
Could it be that high hydrostatic pressures within the alveolus inhibit stem cell differentiation and mammary epithelial cell proliferation?
The NDC mechanobiological model builds on new research about the mechanobiology of the human and murine lactating mammary gland, and the role of mechanosensing in the mammary gland immune response, to propose a complex biological systems perspective. The mechanical effects of intra-alveolar and intra-ductal hydrostatic pressures and extracellular matrix tension (the stromal pump of milk ejection) are proposed to be the dominant regulators of the dynamic homeostasis of the lactating breast, in the context of an endocrine hormonal milieu which supports mammary stem cell differentiation and proliferation.
You can find out about mammary stem cell differentiation and proliferation here.
Recommended resources
Mechanical pressures are the engine room of breastfeeding and lactation
The NDC mechanobiological model explains clinically inflamed lactating breast stroma
Adipocytes and mechanical sensing
Selected references
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