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.

Tissues that regenerate from stem cells

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.

Tissues that regenerate without stem cells

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.

Tissue repair through wound healing

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.

Using genetics to understand regeneration

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.

Environmental regulators of regeneration

Similar to how genes regulate regeneration, CRI researchers are examining how environmental factors such as diet and metabolism also influence regeneration.

Interactions between the clinic and the lab

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.

Hao Zhu, M.D., Director TRP

Defined cellular contributions to liver homeostasis and genetic regulators of liver regeneration.

Michalis Agathocleous, Ph.D.

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

Prashant Mishra, M.D., Ph.D.

Determined how mitochondrial behavior controls tissue homeostasis and repair.

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.

Benjamin Ohlstein, M.D., Ph.D.

Discovered intestinal epithelial stem cells in Drosophila and a novel mechanism of stem cell division.

Featured Discoveries

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

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

February 2022

New research finds muscle tissues absorb damaged stem cells

Mishra lab: Discovered that damaged muscle stem cells are eliminated by being absorbed into existing muscle fibers. This demonstrates a new mechanism by which muscles maintain healthy stem cells that are able to sustain tissue regeneration. Nature Aging 2, 155-169

February 2021

Scientists identify cells responsible for liver tissue maintenance and regeneration

Zhu lab: Identified the cells responsible for liver maintenance and regeneration and pinpointed their location within the liver. These midlobular hepatocytes in zone 2 give rise to new hepatocytes during growth, homeostasis, and regeneration. Science 371:eabb1625

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

April 2019

Researchers show that mutations in human livers can promote tissue regeneration

Zhu lab: Found that genetic mutations accumulate in the adult liver as a result of chronic liver damage. A subset of these mutant clones promote tissue regeneration without promoting liver cancer, demonstrating that somatic mutations are sometimes selected for their ability to promote tissue regeneration. Cell 177, 608-621

August 2017

CRI scientists discover vitamin C regulates stem cell function and suppresses leukemia development

Morrison lab: Discovered that blood-forming stem cells take up unusually high levels of vitamin C, which regulates their function and suppresses the development of leukemia. Good vitamin C nutrition could be important to suppress the development of leukemia in people with clonal hematopoiesis, a common pre-leukemic condition. Nature 549, 476-481

December 2016

CRI scientists discover new bone-forming growth factor that reverses osteoporosis in mice

Morrison lab: Discovered a new bone-forming growth factor, Osteolectin (Clec11a), which is necessary for the maintenance of adult skeletal bone mass and which can systemically promote bone formation when injected into mice, including mice with osteoporosis. eLife 5:e18782

November 2015

CRI identifies emergency response system for blood formation

Morrison lab: Identified a specialized microenvironment in the spleen that supports emergency blood-cell formation (extramedullary hematopoiesis) when blood cell production in the bone marrow is inadequate. Nature 527, 466-471

September 2015

CRI scientists see through bones to uncover blood-forming stem cell details

Morrison lab: Used a tissue-clearing technique to identify the location of blood-forming stem cells in the bone marrow, improving our understanding of the microenvironment in which they reside. Nature 526, 126-30

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

March 2014

Researchers discover a method of measuring protein synthesis in adult stem cells

Morrison lab: Discovered a method of measuring protein synthesis in adult stem cells. This demonstrated that stem cells synthesize protein more slowly than other progenitors, likely to maintain the quality of their proteome. Nature 509, 49-54

June 2013

CRI scientists identify distinct subsets of hematopoietic stem cells and multipotent progenitors

Morrison lab: Found new markers to distinguish biologically distinct subpopulations of stem cells and multipotent progenitors in the blood-forming system. This study also demonstrated that all blood-forming stem cells reside in niches associated with blood vessels in the bone marrow. Cell Stem Cell 13, 102-16

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

January 2012

Blood-forming stem cells’ growth identified in first CRI breakthrough

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

Inside CRI Newsletter

Stay up-to-date with our latest discoveries and news by subscribing to our quarterly email newsletter.