Amino Acid Transporters: Roles for Nutrition and Signalling in Embryonic and Induced Pluripotent Stem Cells

Abstract

Amino acids serve both to nourish and signal 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 of the cloned transporters are listed in solute carrier tables for easy access online (http://slc.bioparadigms.org/). It is more difficult to decide as to which transporters are expressed in a given tissue, and their transport and signalling functions will likely continue to emerge long after all of the transporters have been identified. These ongoing investigations of transporter identification and function for embryonic and induced pluripotent stem cells are illustrated. Surprisingly, characterisation of amino acid transport in these cells is in its infancy. Thus, they serve as an experimental model for investigating the expression of known and novel transporters.

Key Concepts:

  • At least 55 genes encode amino acid transporters in a minimum of 10 gene families (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.

  • Stem cells serve as an experimental model for investigating the expression of known and novel transporters.

  • Threonine uptake and glutamate exodus from stem cells via transporters each fosters cellular proliferation.

  • Glutamate exodus from stem cells is needed to stimulate glutamate receptors.

  • Proline uptake by stem cells promotes their differentiation.

  • mTOR signalling in stem cells is necessary for both proline‐induced differentiation and threonine‐induced proliferation.

  • Both threonine and glutamate promote stem cell proliferation by enhancing the expression of cMyc.

  • Threonine and glutamate likely foster proliferation in human as well as mouse stem cells.

Keywords: amino acid transport systems; amino acid signalling; blastocyst inner cell mass; embryonic stem cells; induced pluripotent stem cells

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. CAT2 knockout mice (and embryos) do not express a functional CAT2 protein (slc7a2 product). System b+1 activity was measured as defined previously (Van Winkle, ). The mean (±S.E.) activities shown were each calculated from 6 to 13 determinations obtained in 3–6 independent experiments. The total system b+1 activity in one‐cell embryos from CAT2 knockout mice was significantly lower than the activity in embryos from otherwise genetically similar control mice as determined in a group comparison t‐test (p<0.01). 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 b1+ 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.

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.

Data from Tables 2 and 5 of Van Winkle and Dickinson 1995.
Figure 3. Weak inhibition of [3H] Pro uptake by l‐Thr and MeAIB.
Figure 4. Partial inhibition of [3H] Pro uptake by l‐Thr and MeAIB.
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Further Reading

Bilic J and Izpisua Belmonte JC (2012) Concise review: Induced pluripotent stem cells versus embryonic stem cells: close enough or yet too far apart? Stem Cells 30: 33–41.

Bröer S (2008) Amino acid transport across mammalian intestinal and renal epithelia. Physiological Reviews 88: 249–286.

Bröer S and Palacín M (2011) The role of amino acid transporters in inherited and acquired diseases. Biochemical Journal 436: 193–211.

Hindley C and Philpott A (2013) The cell cycle and pluripotency. Biochemical Journal 451: 135–143.

Puri MC and Nagy A (2012) Concise review: embryonic stem cells versus induced pluripotent stem cells: the game is on. Stem Cells 30: 10–14.

Sommer CA and Mostoslavsky G (2013) The evolving field of induced pluripotency: recent progress and future challenges. Journal of Cellular Physiology 228: 267–275.

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Van Winkle, Lon J(Sep 2013) Amino Acid Transporters: Roles for Nutrition and Signalling in Embryonic and Induced Pluripotent Stem Cells. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000011.pub3]