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Tissue Regeneration Program

CRI’s Tissue Regeneration Program (TRP) seeks to understand and advance our ability to repair tissues damaged by age, disease, and trauma.

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Our Approach to Tissue Regeneration

CRI scientists use multiple approaches to improve our understanding of tissue regeneration.

Stem cells are responsible for the regeneration of a number of tissues, including the blood, intestinal epithelium, and muscle, but much remains unknown about how this occurs. CRI scientists have made many fundamental advances in isolating and characterizing stem cells from multiple tissues as well as their genetic, biochemical, and metabolic features. Stem cells reside in specialized microenvironments, or niches, in tissues. CRI scientists have identified the location and cellular composition of stem cell niches in adult hematopoietic tissues.

Some organs, such as the liver, contain differentiated cells that can self-renew and regenerate after injury. We identify the cells that contribute to regeneration in these tissues, elucidate the mechanisms that regulate this, and study the implications for cancer risk in chronically injured tissues.

Many human tissues have limited repair capacity or are subjected to chronic injuries that exhaust their repair capacity. Under these circumstances, some mammalian tissues resort to wound healing processes that involve inflammation and scar formation. In some situations, wound healing is overexuberant and exacerbates the condition that elicited the regenerative response. Chronic injury and wound healing are major causes of human disease, and multiple CRI labs are trying to understand how these processes are regulated.

CRI scientists have found recurrent somatic mutations that are selected for their capacity to enhance tissue regeneration but that are not observed in cancers from the same tissue. This changes our understanding of the biological significance of somatic mutagenesis. Previously, it had been assumed that recurrent somatic mutations were selected for their ability to contribute to the development of cancer. This discovery opens a new way of identifying mechanisms that regulate tissue regeneration and raises the possibility of promoting the regeneration of chronically damaged tissues through drug or gene therapy.
Similar to how genes regulate regeneration, CRI researchers are examining how environmental factors such as diet and metabolism also influence regeneration.
CRI integrates science with medicine and constantly seeks to learn from patients. The TRP will interface with Children’s Medical Center Dallas, UT Southwestern clinical departments, and Parkland Hospital to sequence tissues from patients with tissue regeneration phenotypes to identify mutations that might influence regeneration. Just as identifying germline genetic variants has yielded discoveries that transformed medicine, the discovery of somatic mutations could transform our approach to studying tissue regeneration.

TRP Faculty

CRI has a track record of making discoveries in diverse areas related to stem cell function and tissue regeneration.

Headshot of Michalis Agathocleous, Ph.D.

Michalis Agathocleous, Ph.D.

Pioneered the development of techniques to measure metabolites in stem cells and other rare cell populations isolated from tissues.
Headshot of Sean Morrison, Ph.D.

Sean Morrison, Ph.D.

Discovered mechanisms of hematopoietic stem cell self-renewal and the location and cellular composition of niches for stem cells in hematopoietic tissues.

Featured TRP Discoveries

From left: Hao Zhu, M.D., Professor in Children’s Medical Center Research Institute at UT Southwestern (CRI) and of Pediatrics and Internal Medicine at UT Southwestern, and Zhu Lab researchers Roger Liang, B.S., UT Southwestern Perot Family Scholar Medical Scientist Training Program graduate student; Zhijie Li, Ph.D., postdoctoral fellow; and Jason Guo, B.S., UT Southwestern medical student.
Regenerative Medicine
November 2025

Zhu Lab shows location matters for liver cancer’s origins

Zhu Lab: Scientists discovered liver cancers arise in specific metabolic zones, where premalignant cells exploit location-specific genes that promote cell survival by chemical detoxification. While hepatocytes in different zones have vastly different gene expression, scientists did not previously know where liver cancers most frequently arise. CRI Researchers discovered cells with Ctnnb1 and Arid2 mutations were preserved in zone 1 but disappeared in zone 3. Unexpectedly, Ctnnb1/Arid2-driven cancers were much more likely to arise in zone 3 than in zone 1 in aged mice. This zonal preference was significant because it also applied to other types of liver cancer caused by different mutations. Science 391:eadv7129
A stock photo of a team of surgeons filtrating bone marrow in an operationg room. Both people are in full scrubs.
Regenerative Medicine
December 2024

Morrison Lab links hematopoietic cell transplant deaths to beta-blocker use

Morrison Lab: Previous Morrison Lab research discovered β2- and β3-adrenergic receptor signaling are needed for hematopoietic stem cells to regenerate after chemo or radiation therapy. CRI scientists discovered patients are at increased risk of death if they take certain previously prescribed beta-blockers in the weeks after an allogeneic hematopoietic cell transplant. Non-selective beta-blockers impaired hematopoietic regeneration, but b1-selective inhibitors did not. Cancer Discovery 15, 748-66
(Left) Julia Phan, Ph.D., and Sean J. Morrison, Ph.D., Director of Children’s Medical Center Research Institute at UT Southwestern and Professor of Pediatrics, stand side-by-side in the lab.
Regenerative Medicine
October 2024

Morrison Lab discovers ancient viral DNA activates blood cell production during pregnancy, after bleeding

Morrison Lab: Scientists discovered retrotransposons are activated during pregnancy and after significant bleeding in blood-forming stem cells to increase blood cell production. This is an important step toward defining the purpose of “junk DNA” in humans. Retrotransposon expression promotes stem cell division by activating the immune sensors, cGAS and STING, which induce an interferon response to stimulate blood cell production. Science 386:eado6836
Microscope snapshot of cancer cells that have been dyed to illuminate the target of their research.
Metabolism, Regenerative Medicine
June 2024

Metabolic inflexibility keeps damage at bay during liver regeneration

Mishra lab: Researchers identified a type of metabolic inflexibility during liver regeneration that prevents cells with dysfunctional mitochondria from proliferating, which demonstrates one way regenerative cells root out damage. When their mitochondria are damaged, hepatocytes turn on PDK4, a metabolic enzyme that stops the cells from shifting to an alternative source of acetyl-CoA, so they can’t proliferate. Science 384:eadj4301
Graphic illustration showing lineage tracing of mutant clones in NASH, MOSAICS platform for NASH gene discovery and liver-wide knockout validation.
Regenerative Medicine
April 2023

Mutant clones in the liver may fight fatty liver disease

Zhu lab: Showed that clones of hepatocytes containing somatic mutations are selected for their ability to protect against the damaging effects of fatty liver disease. The Zhu lab thus established methods by which adaptive pathways that ameliorate the effects of metabolic disease can be identified. Cell 186, 1968-1984
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