Biology subjects

Kwarteng, E. O.

Publications and source records attributed to Kwarteng, E. O..

3 recordsLinked to original sources

bioRxiv2026

Loss of TCA cycle turning promotes stem cell function

The citric acid cycle (TCA cycle) is the common terminal pathway for the oxidation of all nutrients. Citrate oxidation to oxaloacetate produces CO2, and citrate synthase (CS) uses nutrient-derived acetyl groups to regenerate citrate and fuel cycle turning. However, the essentiality of cycle fueling and turning in vivo remains unclear. Here we use hematopoiesis, the most proliferative system in the body, as a model to show that, contrary to common assumptions, TCA cycle turning is dispensable for respiration, survival, and proliferation of stem and progenitor cells in vivo, and its loss promotes stem cell function. Hematopoietic-specific Cs deletion in adult mice blocked citrate cycling without reducing the frequency of hematopoietic stem (HSC) and progenitor cells. HSCs and progenitor cells adapted to TCA cycle loss by markedly increasing nutrient consumption and biosynthesis. Disruption of cycle turning increased HSC regeneration, myeloid progenitor proliferation, and myelopoiesis in vivo. HSCs without a turning TCA cycle outcompeted wild-type HSCs within the same environment. The effect of CS deletion on HSC function was not phenocopied by genetic ablation of cytosolic citrate use and was rescued by ablation of glutamine use in biosynthesis. Therefore, TCA cycle turning restrains nutrient uptake, biosynthesis, cell proliferation, and stem cell function. These results suggest an explanation for the reduction in cycle activity observed in many normal proliferating cells and cancer cells.

biochemistry↗

bioRxiv2026

Stem cell function in vivo is supported by an alternative glycolysis endpoint

Carbohydrates are classically catabolized by fermentation or oxidation, a choice that impacts many cellular functions including proliferation. Proliferating cells including somatic stem and progenitor cells are thought to favor fermentation over oxidation, and most proliferating cells in vitro depend on lactate production. However, it has not been tested if fermentation and oxidation are the universal obligatory terminal fates for carbohydrates in vivo because the key enzymes, lactate dehydrogenase (LDH) and pyruvate dehydrogenase (PDH), have not been simultaneously deleted in any cell type. Here we show that both fermentation and oxidation are dispensable for the survival and function of hematopoietic stem cells (HSC). Combined LDHA and LDHB deletion to ablate LDH did not impair HSC function, suggesting that HSCs and rapidly proliferating hematopoietic progenitors surprisingly do not require fermentation. Combined LDHA, LDHB, and PDH deletion abolished both glucose oxidation and fermentation, but did not impair HSC function. Glycolysis was preserved, suggesting the operation of an alternative endpoint. LDH/PDH-deficient HSCs terminated glycolysis through pyruvate export. Pyruvate export by HSCs and progenitors was a physiological response to changing nutrient levels. Quadruple deletion of LDHA/B, PDH, and the pyruvate transporter MCT1 impaired HSC function. This suggested that an essential role of glycolysis termination is not to produce acetyl-CoA or lactate but to remove pyruvate. Therefore, in contrast to classical theories and to in vitro metabolism, carbohydrate metabolism in vivo does not require oxidation or fermentation but can terminate directly in pyruvate export, and this alternative pathway is sufficient to support stem cell function.

biochemistry↗

bioRxiv2025

Inhibition of IL2Rβ-dependent STAT5 activity supports T-cell stemness and augments antitumor efficacy of CD8+ T cells by preventing T-cell exhaustion

CD8+ T-cell exhaustion is a leading cause of adoptive cell therapy (ACT) failure. In contrast, maintaining a stem-like state correlates with better expansion, persistence, and anti-tumor activity of infused T-cell products. IL-2 is extensively used in ACT protocols given its ability to expand T-cell populations. Yet, IL-2 drives more differentiated and exhausted states, diminishing the quality of T-cell products. Understanding how cytokines of the IL2R family drive T-cell differentiation is essential to ultimately design optimal ACT protocols, safeguarding stem-like programs while ensuring sufficient T-cell expansion. Here, we show that cytokine signaling through IL2R{beta} supports more differentiated exhausted T cells in chronic lymphocytic choriomeningitis infection. Similarly, high levels of IL-2 and IL-15 in vitro foster heightened differentiation and exhaustion of cells for adoptive cell therapy. In contrast, absence of IL2R{beta} in vivo or transient inhibition of Janus kinase 3 (JAK3) or signal transducer and activator of transcription 5 (STAT5) in vitro favors features of T-cell stemness. Transcriptional analyses of in vitro expanded T cells further reveal that inhibition of STAT5 sustains a stemness program, which correlates with better antitumor activity in a mouse melanoma model. When applied to a human CAR T expansion model, inhibition of STAT5 supports memory progenitor differentiation and limit inhibitory receptor expression. These results demonstrate that continuous exposure to high levels of cytokines, such as IL-2 and IL-15, constrain CD8+ T cells towards more advanced states of exhaustion. In contrast, limiting cytokine signaling using specific kinase inhibitors preserves stem-like T-cell programs and enhance the quality of ACT products. One Sentence SummarySustained IL-2/IL-15 signaling drives CD8+ T-cell exhaustion while JAK3/STAT5 inhibition preserves stemness, boosting adoptive cell therapy efficacy.

immunology↗