The hormetic morphogen theory of curvature and the morphogenesis and pathology of tubular and other curved structures

Abstract

In vitro, morphogens such as transforming growth factor (TGF)-beta can up-and down-regulate cell growth at low and high concentrations respectively, i.e. they behave like hormetic agents. The hormetic morphogen theory of curvature proposes that in vivo tissue gradients of such morphogens secreted by source cells determine the fate of cells within their gradient fields (field cells) and that morphogen-induced amplitude modulation of field cell mitochondrial adenosine triphosphate (ATP) generation controls field cell growth along the morphogen gradients: At the high concentration end of gradients, field cell ATP generation and field cell growth is reduced. With declining concentrations along the rest of the gradients field cell ATP and growth is progressively less reduced until an equidyne point is reached, beyond which ATP generation and growth gradually increases. Thus, the differential growth rates along the gradients curve the tissue. Apoptosis at very high morphogen concentrations enables lumen and cavity formation of tubular, spherical, cystic, domed, and other curved biological structures. The morphogen concentration, the gradient slope and the hormesis responses of field cells determine the curvature of such structures during developmental morphogenesis, tissue remodeling and repair of injury. Aberrant hormetic morphogen signaling is associated with developmental abnormalities, vascular diseases, and tumor formation.

Keywords: Curvature; atherosclerosis; cancer; development; gradients; hormesis; hormetic morphogen; morphogenesis.

FIGURE 1

In vitro hormesis: Graphs illustrating hormetic growth responses induced by transforming growth factor (TGF)-β. Low concentrations stimulate and high concentrations inhibit growth. Left curve illustrates an approximation of data published by McAnulty et al. (1997). Right curve, data from my laboratory (Qui 1995; Fosslien et al. 1997): Proliferation of smooth muscle cells (SMCs), average of in vitro triplicate measurements. Controls (C) represents the in vitro growth rates of corresponding non-supplemented cells. ΔG%: percent modulation of cell growth compared to controls. At the equidyne point (EQP), stimulation and inhibition of the growth rates by TGF-β are in balance and equal to the basic growth rates of control cells. For further details see text.

FIGURE 2

Curvature formation by hermetic morphogen; single concentration gradient shown on top left, MGH (hexagon) indicates morphogen gradient head; left middle graph illustrates a theoretical hormetic response curve of field cells to the morphogen gradient (compare Figure 1); bottom left graph illustrates a linearized part of the induced growth gradient (ΔG) along the morphogen gradient. Right panel: concave curvature of mural section by radial gradients of the hormetic morphogen (blue arrows) that induce declining inhibition of mural cell growth from morphogen gradient heads up to the morphogen equidyne line (MEL), beyond which mural cell growth is gradually stimulated. EQC: Morphogen equidyne concentration; EQP: equidyne point of field cell hormesis curve. At a mural thickness (δ) of 0.5 mm and a 20% morphogen gradient-induced growth difference (compare Figure 1), the resulting curvature of the wall would result in a theoretical vessel internal diameter of 5 mm.

FIGURE 3A

Tubulogenesis: Role of energetics in curvature formation of a tubular or cystic structure. Left panels illustrate different single mural gradients of a hormetic morphogen radiating through mural tissue with thickness δ. The hormetic morphogen gradient (top left) modulates field cell ATP generation thus forming a mural ATP gradient (middle left) that induces a mural growth gradient ΔG (bottom left) along the mural morphogen gradient. Right: The radial mural growth gradients curve the mural tissue. Tissue gradients of hormetic morphogens can thus induce concave tissue curvatures as seen from the high concentration end of morphogen gradients.

FIGURE 3B

Growth gradient (G) regulation of curvature of tissue with thickness δ and at stable field cell hormesis: The morphogen concentration at the heads of the radial gradients and the slope of the gradients determine the radius of curvature and thereby the tube or cyst diameter. Top panel, ΔG₀: no growth differential (left), no curvature (right); middle panel: ΔG₁, mild growth differential, mild slope (left), mild curvature (right); bottom panel: ΔG₂, large growth differential, steeper slope (left), more curvature (right). EQDL: equidyne line.

FIGURE 4

Evidence-based and theoretical effects of hormetic morphogen radial gradients (blue arrow) diffusing from central pellet (blue) soaked in the morphogen. A: Very high concentrations of morphogen causes formation of a pellet-surrounding zone (yellow) of cell disintegration (apoptosis, necrosis), which is itself surrounded by a coaxial “mural” zone consisting of an inner zone of growth inhibition (red) and an outer zone of growth stimulation (green) separated by an equidyne line (dotted line). B: Graph illustrates the hormetic morphogen concentration along one radial (blue) gradient d (d=distance) shown in A; small circle illustrates the location of pellet. C. Graph of inhibition (red) and stimulation (green) of growth along concentrations gradient shown in B. Apoptosis/necrosis illustrated as negative (yellow arrow) growth (disintegration of cells). D: Graph of a single mural growth gradient.

FIGURE 5

Evidence-based examples of regulation of mitochondrial ATP synthesis by charge regulators (DIF-1 and O₂) that can limit the amount of fuel-energy conversion to mitochondrial inner membrane potential (Δψ_m), or via amplitude modulation of coupling to ATP synthesis by hormetic morphogens (TGF-β and auxin), or by uncoupling of Δψ_m energy, either via opening of membrane pores by apoptotic concentrations of TGF-β or by TGF-β-induced increases in uncoupling protein (UCP) via cyclooxygenase induction (not shown). TGF-β can modulate ATP synthesis by regulating the expression of adenine nucleotide transporters (ANT1 and ANT2). Auxin (IAA) can modulate ADP phosphorylation (For a more complete analysis see Fosslien 2008).

FIGURE 6

Vascular pathologies: Evidence-based and theoretical diagram illustrating selected aberrations of parts of TGF-β₁-gradient-induced curvature formation. TGF-β₁, secreted by morphogen source cells and activated by activator (ACTV), form diffusion/perfusion (D/P) gradients that signal via receptor complexes consisting of TGF-β Type II receptors and endoglin (ENG) and then via inhibitory (top, ALK5, Smad2/3) and stimulatory (bottom, ALK2 and Smad1/5/8) pathways, reducing and stimulating mitochondrial synthesis of ATP respectively. Radial hormetic morphogen gradients up- and down-regulate field cell ATP synthesis. Amplitude modulation of field cell ATP along the gradients induces differential growth (ΔG) along the tissue gradients (growth gradients), which induces tissue curvature. HHT: hereditary hemorrhagic teleangiectasia; VMIM: vascular mimicry. For further explanation see text.