A review of the important central role of altered citrate metabolism during the process of stem cell differentiation

Abstract

Stem cells are highly proliferating cells that have the potential for differentiation leading to the development of specialized functional cell types. The process of stem cell differentiation requires an increase in the recruitment and population of the undifferentiated stem cells, which are then differentiated to specific functional cell types. Genetic/metabolic transformations in the cellular intermediary energy metabolism are required to provide the bioenergetic, synthetic, and catabolic requirements of the stem cells during this process. However, the identification of the intermediary energy metabolism pathways and their alterations during the proliferation and differentiation of stem cells remain largely unknown; mainly due to the lack of attention and/or required research that focuses on this relationship. In the absence of such information, a full understanding of the factors and conditions required to promote stem cell differentiation leading to development of normal functional metabolic specialized cells cannot be achieved. The purpose of this review is to provide the background and bring attention to the essential relationship of altered cellular intermediary metabolism in the context of the process of stem cell proliferation and differentiation. Citrate metabolism is central to the genetic and metabolic transformation leading to the development of the specialized functional cells. This review identifies the involvement of altered citrate metabolism and the associated genetic alterations of key pathways, enzymes, and transporters; as well as the bioenergetic implications. The importance is emphasized for identification and employment of required conditions to insure that the process of experimental stem cell differentiation results in the development of specialized cells that represent the functional metabolic characteristics and capabilities of their native specialized cells. This is an essential requirement for the successful application of stem cell therapy and regenerative medicine for many pathological conditions.

Keywords: Citrate metabolism; differentiation and proliferation; glycolysis; krebs cycle; osteoblast and bone formation adipogenesis; osteogenesis; stem cells.

Figure 1

A representation of the stem cell differentiation process and the requirements for genetic/metabolic transformations in stem cell intermediary metabolism. A= the proliferation phase for increased population of undifferentiated stem cells. B= the differentiation phase leading to specific functional cell types (b1,b2, b3, b4).

Figure 2

A metabolic chart of the pathways of intermediary metabolism. The Krebs cycle is identified by black circle; and shows its central position from which essentially all aerobic metabolic pathways arise or converge.

Figure 3

A typical representation of the sequence of reactions in the Krebs cycle in the oxidation of glucose. Not shown is the conversion of 1 mole of glucose to 2 moles of pyruvate for mitochondrial oxidation. PDH=pyruvate dehydrogenase; CS=citrate synthase; Acon= m-aconitase.

Figure 4

Representation of the citrate pathways in cell metabolism. A. Citrate oxidation via the Krebs cycle. B. Citrate export from mitochondria to cytosol for lipogenesis. C. Citrate export from mitochondria to cytosol for secretion into the extracellular fluid. CTP= citrate transporter protein.

Figure 5

The equilibrium reaction of m-aconitase in typical mammalian cells. CS=citrate synthase; IDH=isocitrate dehydrogenase; Acon= m-aconitase; Cit=citrate; Cis acon= cis-aconitate; Isocit=isocitrate; AccoA= acetylCoA; OAA=oxalacetate.

Figure 6

The utilization of citrate for de novo lipogenesis in the genetic/metabolic transformation of highly proliferating undifferentiated stem cells. CTP= citrate transporter protein; ACL=ATP-citrate lyase; MDH=malic dehydrogenase.

Figure 7

Sparing effect on citrate oxidation by possible alternative sources of cytosolic acetylCoA for de novo lipogenesis in highly proliferating stem cells.

Figure 8

A glutamine/glutamate pathway for citrate synthesis for de novo lipogenesis in highly proliferating stem cells. ME=malic enzyme; MDH= malic dehydrogenase; GLASE=glutaminase; GDH= glutamic dehydrogenase; ACL=ATP-citrate lyase; CTP=citrate transport protein.

Figure 9

The pathway for citrate production by differentiated osteoblasts for citrate incorporation into bone. Red represents the upregulated events; and the black dashed pathway represents the truncated Krebs cycle. ASP=aspartate; ASTR= aspartate transporter; MAAT=mitochondrial aspartate aminotransferase; CTP=citrate transporter protein; ZIP= zinc uptake transporter; ISF=interstitial fluid.