Amino Acid Transporters: Roles for Nutrition, Signalling and Epigenetic Modifications in Embryonic Stem Cells and Their Progenitors

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Amino Acid Transporters: Roles for Nutrition, Signalling and Epigenetic Modifications in Embryonic Stem Cells and Their Progenitors

Lon J Van Winkle, Rocky Vista University, Parker, Colorado, USA
Rebecca Ryznar, Rocky Vista University, Parker, Colorado, USA

Published online: October 2019

DOI: 10.1002/9780470015902.a0000011.pub4

Full Article on Wiley Online Library

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Abstract

Amino acids serve both to nourish and as signalling molecules in cells and, consequently, so do their biomembrane transporters. In fact, some of these transporters may initiate signalling while transporting an amino acid substrate rather than serving simply to transport a signalling molecule. Most amino acid transporters now appear to have been cloned, and virtually all the cloned transporters are listed in solute carrier tables for easy access online. The characteristics of the transporters as they are expressed normally in cells do not always correspond to the characteristics of cloned transporters, however, and their transport and signalling functions will likely continue to emerge long after all transporters have been identified. For example, amino acids are metabolised to products that regulate DNA and specific epigenetic histone modifications in embryonic stem cells in order to maintain their proliferation and pluripotency. Alterations in these histone modifications may be expressed in a transgenerational manner and include both intracellular and extracellular histone actions.

Key Concepts

At least 60 genes in 12 gene families encode amino acid transporters (see tables at http://slc.bioparadigms.org/).
An amino acid may be listed as a substrate for a cloned transporter in these tables even though its transport has not been studied in detail.
The characteristics of cloned amino acid transporters may not correspond to the ways they function in cellular physiology.
Embryonic stem cells and their progenitors require specific environmental amino acids to remain undifferentiated.
Metabolism of the required amino acids produce products that regulate DNA and specific epigenetic histone modifications needed to maintain stem cell proliferation and pluripotency.
Mouse embryonic stem cells take up the threonine they require via at least three obligate exchange amino acid transporters.
Human embryonic stem cells take up the methionine they need via amino acid transporter(s) that warrant full characterisation.
A maternal low protein diet during pre‐ and peri‐implantation development of embryos likely alters epigenetic DNA and histone modifications in embryonic stem progenitor cells.
These epigenetic DNA and histone alterations help to cause metabolic syndrome and related disorders, and they are likely transgenerational.
Extracellular as well as intracellular histone actions may influence transgenerational phenotype.

Keywords: amino acid transport systems; amino acid signalling; one‐carbon metabolism; blastocyst inner cell mass; embryonic stem cells; transgenerational epigenetic histone modification

	Figure 1. One‐cell embryos that do not express the slc7a2 product (CAT2 knockout embryos) have reduced system b⁺₁ activity relative to one‐cell embryos from genetically similar control mice. The reduction in activity is attributed to the lack of functional CAT2 expression, whereas the activity remaining in one‐cell embryos from CAT2 knockout mice is attributed to CAT1 (slc7a1 product) and, possibly, CAT3 (slc7a3 product) expression (Table ). CAT1, CAT2 and probably CAT3 normally are expressed throughout preimplantation development. The lack of reduction in system b⁺₁ activity in CAT2 knockout two‐cell conceptuses is attributed to an increased expression of CAT1 or CAT3 upon activation of the embryo genome at the late one‐cell stage to compensate for the missing CAT2 activity. See text for further discussion. Van Winkle . Reproduced with permission of John Wiley & Sons.
	Figure 2. Changes in the aspartate (Asp), glutamate (Glu) and glutamine (Gln) content of preimplantation mouse embryos during development in vivo. Stages of development at various times after fertilisation are 35 h = 2‐cell, 59 h = 4‐ to 8‐cell, 83 h = earlier blastocyst and 107 h = later blastocyst. Van Winkle . Reproduced with permission of John Wiley & Sons.
	Figure 3. Mouse blastocysts hydrolyse protein in order to accumulate threonine (Thr). Thr, but not Val, Leu or Ile, accumulated in blastocysts in statistically significant amounts both in vivo (solid lines) and in vitro (dashed lines) between 83 and 107 h after fertilisation (p < 0.01). Since amino acids were not supplied in the culture medium as blastocysts developed from the two‐cell stage in vitro, they could accumulate essential amino acids, such as Thr, only if they hydrolysed protein, such as bovine serum albumin, in the medium.
	Figure 4. Percent uptake of 50 uM [³H]‐Thr in the presence of 140 mM NaCl and 10 mM of the amino acid indicated. More complete inhibitors (p < 0.0001) included Met through Cys, but Leu through Gln inhibition was also statistically significant (p < 0.05). Formisano and Van Winkle . Licensed under CC‐BY.
	Figure 5. Mouse feeder cells hydrolyse protein to generate essential amino acids (p < 0.01), but hES cells consume only methionine in a statistically significant manner (p < 0.05).
	Figure 6. Inhibition of Na⁺‐dependent 50 uM [³H]‐Pro uptake by various amino acids resembles inhibition of uptake via system A transporters. (See text).
	Figure 7. Model for Thr accumulation against its total chemical potential (“concentration”) gradient by mES cells. ATP hydrolysis by Na⁺/K⁺ ATPase drives K⁺ uptake into and Na⁺ extrusion from cells. The resultant Na⁺ gradient drives Ala uptake into cells via Na⁺‐dependent system A. The resultant Ala gradient then drives Thr uptake via obligatory system ASC amino acid exchange. Thr dehydrogenase (TDH) helps to metabolise Thr to Gly and acetyl CoA in mES cells, and these substrates drive epigenetic DNA and histone modifications in the cells. (See text for more details).

Article Title:	Amino Acid Transporters: Roles for Nutrition, Signalling and Epigenetic Modifications in Embryonic Stem Cells and Their Progenitors
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