Research Areas

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.

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.

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

June 2024
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
April 2023
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
October 2022
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
February 2021
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
June 2014
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
February 2013
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
January 2012
Morrison lab: Identified the microenvironment, or niche, in which blood-forming stem cells are maintained within the bone marrow, a long-standing goal in the field of stem cell biology. This study also reported the discovery of Leptin Receptor-expressing stromal cells in the bone marrow that are the main source of growth factors required for the maintenance of blood-forming stem cells. Nature 481, 457–62

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