NDC mechanobiological model #2: mechanical signaling triggered by milk ejection increases stem cell differentiation and proliferation, upregulating breastmilk secretion

"She looked from Leonie to Therese and she smiled. "Of course I fed you both, silly. I had plenty of milk didn’t I …." Rose in her chair by the fire, feet up, blouse undone, a lapful of babies, a shout of joy, the smell of milk, there, my dears, there." Michele Roberts, Daughters of the House p 169

"Flourish ….. To grow luxuriantly, or thrive in growth." The Macquarie Dictionary p 687

The hormonal milieu of lactation prepares the terrain

Many hormones persist post-birth and are thought to contribute to the complex hormonal milieu which makes the cell proliferation of secretory activation and then galactopoiesis possible.

These include reproductive hormones, most prominently prolactin, and metabolic hormones, which act either directly on the lactocyte or by indirectly altering the endocrine response and nutrient delivery to the mammary gland. Metabolic hormones which promote breast milk secretion include glucocorticoids, insulin, insulin-like growth factor, and growth hormone.

Mammary gland stem or progenitor cells constantly differentiate and proliferate

Cell proliferation of the various mammary epithelial cells occurs constantly within the lactating mammary gland. Progenitor stem cells differentiate and proliferate into mammary epithelial cells, in response to the wash of the endocrine hormones which prepare the terrain, including prolactin.

Self-renewing, unipotent and bipotent progenitor cells, or mammary stem cells, can be found through the human mammary gland. Stem cells are found in

• The extracellular matrix, which is recognised as

  • A key component of the mammary gland stem cell niche

  • A local microenvironment which sustains stem cell quiescence and facilitates the maintenance of stem cells through regulated self-replication and retention of multipotency.

• The mammary epithelium (both alveolar and ductal)

• Breast milk.

These cells display extensive renewing capacities at different stages of mammary gland development. They are programmed to develop into either one (unipotent) or both (bipotent) mammary epithelial cells, that is, either luminal (lactocytes or duct lining) epithelial cells or myoepithelial cells, or both. They may also contribute to breast tissue remodelling more broadly, as necessary.

Importantly, the differentiation and proliferation of stem or progenitor cells in the mammary epithelium is also known to be regulated by chemical signalling created by mechanical forces (e.g. tissue stiffness) of the extracellular matrix.

"Dynamic reciprocity in the mammary gland involves bidirectional interactions between epithelial and stromal cells and the extracellular matrix. ... Importantly, Northey et al demonstrated that enhanced mechanical signaling [from the extracellular matrix] ... expands the stem progenitor population in the mammary gland." (Anlas & Nelson 2024 p. 434)

The dominant bioactive factors Feedback Inhibitor of Lactation model does not adequately explain mechanisms of upregulation of milk secretion

The current bioactive factors Feedback Inhibitor of Lactation model does not attempt to elucidate the mechanisms which might upregulate breast milk secretion, other than positing the action of myriad bioactive factors acting backwards from the milk upon the lactocytes, and pointing to the endocrine hormonal milieu including of oxytocin and prolactin.

However, back action from the milk raises multiple questions concerning concentration vs total load, and area of contact between the milk and lactocytes. Oxytocin causes contraction of the alveoli and dilation of the ducts, but is not linked to breast milk yield. Similarly, prolactin levels are not linked to breast milk yield.

NDC mechanobiological hypothesis: pressure effects of milk ejection acts as a stromal pump which stimulates stem cell differentiation and proliferation

Here is an explanation for why increasing the frequency of milk removal increases the volume of breast milk secretion. The NDC mechanobiological model of the upregulation of milk production proposes that frequent contraction of the alveoli and also the increased stromal pressures resulting from ductal dilation during milk ejection (which I have characterised as a stromal pump in my research papers concerning breast inflammation) increases the rate of stem cell differentiation and proliferation?

• Stochastic alveolar contraction, under the influence of contracted myoepithelial cells, places significant mechanical force upon both lactocytes and stem cells.

• Ductal dilation acts as an irregular wave of increased stromal pressures throughout the lactating mammary gland. It has been demonstrated elsewhere (Northey et al using mouse and organoid tissues) that increased extracellular matrix mechanical pressures result in increased progenitor cell proliferation.

There is much that is unknown and which requires research. But the NDC mechanobiological models of both upregulation and downregulation of human breast milk production arise out of and are supported by emerging research, and are preferenced by the principle of Okkam's razor.

Selected references

Anlas AA, Nelson CM. Interplay between hormonal and mechanical signals in mammary morphodynamics. Trends in Cell Biology. 2024;34(6):434-436.

Ivanova E, Le Guillou S, Hue-Beauvais C, Le Provost F. Epigenetics: new insights into mammary gland biology. Genes. 2021;12:https://doi.org/10.d3390/genes12020231.

Liu C, Xu Y, Yang G. Niche inflammatory signals control oscillating mammary regeneration and protect stem cells from cytotoxic stress. Cell Stem Cell. 2024;31(1):89-105.e106.

Northey JJ, Barrett AS, Acerbi I. Stiff stroma increases breast cancer risk by inducing the oncogene ZNF217. The Journal of Clinical Investigation. 2020;130(11):5721-5737.

Stewart TA, Hughes K, Stevenson AJ, Marino N, Ju AL, Morehead M, et al. Mammary mechanobiology - investigating roles for mechanically activated ion channels in lactation and involution. Journal of Cell Science. 2021;134:doi:10.124/jcs.248849.