Theodore Terence Ho

All Publications

• Autophagy maintains the metabolism and function of young and old stem cells NATURE Ho, T. T., Warr, M. R., Adelman, E. R., Lansinger, O. M., Flach, J., Verovskaya, E. V., Figueroa, M. E., Passegue, E. 2017; 543 (7644): 205-+

  Abstract

  With age, haematopoietic stem cells lose their ability to regenerate the blood system, and promote disease development. Autophagy is associated with health and longevity, and is critical for protecting haematopoietic stem cells from metabolic stress. Here we show that loss of autophagy in haematopoietic stem cells causes accumulation of mitochondria and an activated metabolic state, which drives accelerated myeloid differentiation mainly through epigenetic deregulations, and impairs haematopoietic stem-cell self-renewal activity and regenerative potential. Strikingly, most haematopoietic stem cells in aged mice share these altered metabolic and functional features. However, approximately one-third of aged haematopoietic stem cells exhibit high autophagy levels and maintain a low metabolic state with robust long-term regeneration potential similar to healthy young haematopoietic stem cells. Our results demonstrate that autophagy actively suppresses haematopoietic stem-cell metabolism by clearing active, healthy mitochondria to maintain quiescence and stemness, and becomes increasingly necessary with age to preserve the regenerative capacity of old haematopoietic stem cells.

  View details for DOI 10.1038/nature21388

  View details for Web of Science ID 000395688700031

  View details for PubMedID 28241143

  View details for PubMedCentralID PMC5344718

• Autophagy counters inflammation-driven glycolytic impairment in aging hematopoietic stem cells. Cell stem cell Dellorusso, P. V., Proven, M. A., Calero-Nieto, F. J., Wang, X., Mitchell, C. A., Hartmann, F., Amouzgar, M., Favaro, P., DeVilbiss, A., Swann, J. W., Ho, T. T., Zhao, Z., Bendall, S. C., Morrison, S., Göttgens, B., Passegué, E. 2024

  Abstract

  Autophagy is central to the benefits of longevity signaling programs and to hematopoietic stem cell (HSC) response to nutrient stress. With age, a subset of HSCs increases autophagy flux and preserves regenerative capacity, but the signals triggering autophagy and maintaining the functionality of autophagy-activated old HSCs (oHSCs) remain unknown. Here, we demonstrate that autophagy is an adaptive cytoprotective response to chronic inflammation in the aging murine bone marrow (BM) niche. We find that inflammation impairs glucose uptake and suppresses glycolysis in oHSCs through Socs3-mediated inhibition of AKT/FoxO-dependent signaling, with inflammation-mediated autophagy engagement preserving functional quiescence by enabling metabolic adaptation to glycolytic impairment. Moreover, we show that transient autophagy induction via a short-term fasting/refeeding paradigm normalizes glycolytic flux and significantly boosts oHSC regenerative potential. Our results identify inflammation-driven glucose hypometabolism as a key driver of HSC dysfunction with age and establish autophagy as a targetable node to reset oHSC regenerative capacity.

  View details for DOI 10.1016/j.stem.2024.04.020

  View details for PubMedID 38754428

• Cardiogenic control of affective behavioural state. Nature Hsueh, B., Chen, R., Jo, Y., Tang, D., Raffiee, M., Kim, Y. S., Inoue, M., Randles, S., Ramakrishnan, C., Patel, S., Kim, D. K., Liu, T. X., Kim, S. H., Tan, L., Mortazavi, L., Cordero, A., Shi, J., Zhao, M., Ho, T. T., Crow, A., Yoo, A. W., Raja, C., Evans, K., Bernstein, D., Zeineh, M., Goubran, M., Deisseroth, K. 2023

  Abstract

  Emotional states influence bodily physiology, as exemplified in the top-down process by which anxiety causes faster beating of the heart1-3. However, whether an increased heart rate might itself induce anxiety or fear responses is unclear3-8. Physiological theories of emotion, proposed over a century ago, have considered that in general, there could be an important and even dominant flow of information from the body to the brain9. Here, to formally test this idea, we developed a noninvasive optogenetic pacemaker for precise, cell-type-specific control of cardiac rhythms of up to 900beats per minute in freely moving mice, enabled by a wearable micro-LED harness and the systemic viral delivery of a potent pump-like channelrhodopsin. We found that optically evoked tachycardia potently enhanced anxiety-like behaviour, but crucially only in risky contexts, indicating that both central (brain) and peripheral (body) processes may be involved in the development of emotional states. To identify potential mechanisms, we used whole-brain activity screening and electrophysiology to find brain regions that wereactivated by imposed cardiac rhythms. We identified the posterior insular cortex as a potential mediator of bottom-up cardiac interoceptive processing, and found that optogenetic inhibition of this brain region attenuated the anxiety-like behaviour that was induced by optical cardiac pacing. Together, these findings reveal that cells of both the body and the brain must be considered together to understand the origins of emotional or affective states. More broadly, our results define a generalizable approach for noninvasive, temporally precise functional investigations of joint organism-wide interactions among targeted cells during behaviour.

  View details for DOI 10.1038/s41586-023-05748-8

  View details for PubMedID 36859543

• Aged hematopoietic stem cells are refractory to bloodborne systemic rejuvenation interventions JOURNAL OF EXPERIMENTAL MEDICINE Ho, T. T., Dellorusso, P., Verovskaya, E. V., Bakker, S. T., Flach, J., Smith, L. K., Ventura, P. B., Lansinger, O. M., Herault, A., Zhang, S., Kang, Y., Mitchell, C. A., Villeda, S. A., Passegue, E. 2021; 218 (7)

  Abstract

  While young blood can restore many aged tissues, its effects on the aged blood system itself and old hematopoietic stem cells (HSCs) have not been determined. Here, we used transplantation, parabiosis, plasma transfer, exercise, calorie restriction, and aging mutant mice to understand the effects of age-regulated systemic factors on HSCs and their bone marrow (BM) niche. We found that neither exposure to young blood, nor long-term residence in young niches after parabiont separation, nor direct heterochronic transplantation had any observable rejuvenating effects on old HSCs. Likewise, exercise and calorie restriction did not improve old HSC function, nor old BM niches. Conversely, young HSCs were not affected by systemic pro-aging conditions, and HSC function was not impacted by mutations influencing organismal aging in established long-lived or progeroid genetic models. Therefore, the blood system that carries factors with either rejuvenating or pro-aging properties for many other tissues is itself refractory to those factors.

  View details for DOI 10.1084/jem.20210223

  View details for Web of Science ID 000663429700003

  View details for PubMedID 34032859

  View details for PubMedCentralID PMC8155813

• Lysosome activation clears aggregates and enhances quiescent neural stem cell activation during aging SCIENCE Leeman, D. S., Hebestreit, K., Ruetz, T., Webb, A. E., McKay, A., Pollina, E. A., Dulken, B. W., Zhao, X., Yeo, R. W., Ho, T. T., Mahmoudi, S., Devarajan, K., Passegue, E., Rando, T. A., Frydman, J., Brunet, A. 2018; 359 (6381): 1277–82

  Abstract

  In the adult brain, the neural stem cell (NSC) pool comprises quiescent and activated populations with distinct roles. Transcriptomic analysis revealed that quiescent and activated NSCs exhibited differences in their protein homeostasis network. Whereas activated NSCs had active proteasomes, quiescent NSCs contained large lysosomes. Quiescent NSCs from young mice accumulated protein aggregates, and many of these aggregates were stored in large lysosomes. Perturbation of lysosomal activity in quiescent NSCs affected protein-aggregate accumulation and the ability of quiescent NSCs to activate. During aging, quiescent NSCs displayed defects in their lysosomes, increased accumulation of protein aggregates, and reduced ability to activate. Enhancement of the lysosome pathway in old quiescent NSCs cleared protein aggregates and ameliorated the ability of quiescent NSCs to activate, allowing them to regain a more youthful state.

  View details for PubMedID 29590078

  View details for PubMedCentralID PMC5915358

• Metabolic regulation of stem cell function in tissue homeostasis and organismal ageing NATURE CELL BIOLOGY Chandel, N. S., Jasper, H., Ho, T. T., Passegue, E. 2016; 18 (8): 823–32

  Abstract

  Many tissues and organ systems in metazoans have the intrinsic capacity to regenerate, which is driven and maintained largely by tissue-resident somatic stem cell populations. Ageing is accompanied by a deregulation of stem cell function and a decline in regenerative capacity, often resulting in degenerative diseases. The identification of strategies to maintain stem cell function and regulation is therefore a promising avenue to allay a wide range of age-related diseases. Studies in various organisms have revealed a central role for metabolic pathways in the regulation of stem cell function. Ageing is associated with extensive metabolic changes, and interventions that influence cellular metabolism have long been recognized as robust lifespan-extending measures. In this Review, we discuss recent advances in our understanding of the metabolic control of stem cell function, and how stem cell metabolism relates to homeostasis and ageing.

  View details for DOI 10.1038/ncb3385

  View details for Web of Science ID 000380829200001

  View details for PubMedID 27428307

• siRNA Delivery Impedes the Temporal Expression of Cytokine-Activated VCAM1 on Endothelial Cells ANNALS OF BIOMEDICAL ENGINEERING Ho, T. T., You, J., Auguste, D. T. 2016; 44 (4): 895–902

  Abstract

  Leukocyte recruitment plays a key role in chronic inflammatory diseases such as cardiovascular disease, rheumatoid arthritis, and cancer. Leukocyte rolling and arrest are mediated in part by the temporally-regulated surface expression of vascular cell adhesion molecule-1 (VCAM1) on endothelial cells (ECs). In this paper, we engineered a pH-responsive vehicle comprised of 30 mol% dimethylaminoethyl methacrylate (30D) and 70 mol% hydroxyethyl methacrylate (70H) to encapsulate, protect, and deliver VCAM1 small interfering RNA (siRNA). The ability of siRNA to reduce VCAM1 gene expression is in direct opposition to its activation by cytokines. At 12 h post-activation, VCAM1 gene knockdown was 90.1 ± 7.5% when delivered via 30D/70H nanoparticles, which was on par with a leading commercial transfection agent. This translated into a 68.8 ± 6.7% reduction in the surface density of VCAM1 on cytokine-activated ECs. The pH-responsive delivery of VCAM1 siRNA efficiently reduced temporal surface protein expression, which may be used to avert leukocyte recruitment.

  View details for DOI 10.1007/s10439-015-1364-x

  View details for Web of Science ID 000373741800006

  View details for PubMedID 26101035

• Functional evidence implicating chromosome 7q22 haploinsufficiency in myelodysplastic syndrome pathogenesis ELIFE Wong, J. C., Weinfurtner, K. M., Alzamora, M., Kogan, S. C., Burgess, M. R., Zhang, Y., Nakitandwe, J., Ma, J., Cheng, J., Chen, S., Ho, T. T., Flach, J., Reynaud, D., Passegue, E., Downing, J. R., Shannon, K. 2015; 4

  Abstract

  Chromosome 7 deletions are highly prevalent in myelodysplastic syndrome (MDS) and likely contribute to aberrant growth through haploinsufficiency. We generated mice with a heterozygous germ line deletion of a 2-Mb interval of chromosome band 5A3 syntenic to a commonly deleted segment of human 7q22 and show that mutant hematopoietic cells exhibit cardinal features of MDS. Specifically, the long-term hematopoietic stem cell (HSC) compartment is expanded in 5A3(+/del) mice, and the distribution of myeloid progenitors is altered. 5A3(+/del) HSCs are defective for lymphoid repopulating potential and show a myeloid lineage output bias. These cell autonomous abnormalities are exacerbated by physiologic aging and upon serial transplantation. The 5A3 deletion partially rescues defective repopulation in Gata2 mutant mice. 5A3(+/del) hematopoietic cells exhibit decreased expression of oxidative phosphorylation genes, increased levels of reactive oxygen species, and perturbed oxygen consumption. These studies provide the first functional data linking 7q22 deletions to MDS pathogenesis.

  View details for DOI 10.7554/eLife.07839

  View details for Web of Science ID 000373853200001

  View details for PubMedID 26193121

  View details for PubMedCentralID PMC4569895