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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.

Michalis Agathocleous, Ph.D.

Pioneered the development of techniques to measure metabolites in stem cells and other rare cell populations isolated from tissues.

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

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 [online before print]
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
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
Regenerative Medicine
October 2022

Researchers find that different stem cells are responsible for the repair of different kinds of bone injuries

Morrison lab: Identified markers that distinguish skeletal stem cells in the bone marrow from skeletal stem cells on the outside surface of bones and compared their functions. The Leptin Receptor-expressing skeletal stem cells in the bone marrow are responsible for the steady-state production of new bone cells that maintain the adult skeleton and repair certain types of bone injuries. The Gli1-expressing skeletal stem cells on the outside surfaces of bones (in the periosteum) are responsible for fracture repair. Cell Stem Cell 29, 1547-1561
Regenerative Medicine
February 2021

Researchers identify mechanism by which exercise strengthens bones and immunity

Morrison lab: Identified a specialized environment in the bone marrow where new bone and immune cells are produced around arterioles and found that maintenance of this niche, as well as the bone- and immune-forming cells that it contains, requires load-bearing exercise. Together, these findings identify a new way that exercise strengthens bones and immune function. Nature 591, 438-444
Regenerative Medicine
June 2014

CRI finds key to identifying, enriching mesenchymal stem cells

Morrison lab: Found that Leptin Receptor-expressing stromal cells that are a key source of growth factors in the niche for blood-forming stem cells in the bone marrow also include the skeletal stem cells that form the adipocytes and osteoblasts that arise in adult bone marrow. These cells maintain and repair the adult skeleton. Cell Stem Cell 15, 154-68
Regenerative Medicine
February 2013

Scientists identify bone-marrow environment that helps fight infection

Morrison lab: Identified a microenvironment, or niche, in which specialized blood-forming cells produce infection-fighting white blood cells (T cells and B cells) in the bone marrow. This demonstrated that there are distinct locations in the bone marrow that maintain stem cells and restricted blood-forming progenitors in the bone marrow. Nature 495, 231–5
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