【Cell sub-journal】Organ regeneration? Uncover new mechanisms by which bacteria promote liver growth

Bacteria-induced reprogramming reactivates liver progenitor cells and upregulates growth, metabolism, and anti-aging-related markers with minimal changes in aging and tumorigenic genes, suggesting that bacteria hijack homeostatic regeneration pathways to promote neogenesis
.
This may facilitate the unravelling of endogenous pathways that effectively and safely re-engage in liver organ growth with a wide range of therapeutic implications, including organ regeneration and rejuvenation
.

This article is the original of Translational Medicine Network, please indicate the source for reprinting

Author: kope

Despite the potential of in vitro models, organoids, and miniature organs for drug discovery, disease modeling, and regenerative medicine, they cannot model the organ-level complexity
required.
Therefore, despite advances in these methods, there are currently no strategies capable of achieving effective regeneration or rejuvenation
of adult organs in chronic or aging-related human diseases.

Regenerative recovery of hepatocytes

 01 

The liver is a model organ
for the study of growth and regeneration.
Unlike other solid organs, the adult liver has the ability to restore its previous mass after tissue loss, restoring homeostasis
.
In human chronic liver disease, repeated inflammatory damage and parenchymal cell death stimulate the regenerative recovery of hepatocyte masses while producing a wound healing response
.
Cirrhosis still has some regenerative capacity, but it is unlikely to recover completely, and transplantation remains the only treatment
.
Chronic injury is associated with an increased risk of malignancy, which is highest
among chronic viral infections.
The endogenous pathway to regenerate the damaged liver remains poorly described, and failure to understand leads to the lack of a clinical strategy
to promote regeneration.
With the health and financial burden of liver disease rapidly increasing, the lack of this repair strategy is critical
.
In addition, as physiological function declines, an aging liver is more susceptible to progressive diseases
.
Maintaining a healthy liver is essential for healthy aging because it directly or indirectly affects other organ function, but there are no rejuvenating strategies to slow or reverse the decline
in liver function during aging.

Current research into liver regeneration uses short-lived rodent models that require hepatocyte loss to stimulate regeneration, which will stop
when the original liver size is reached.
Once the previous organ size is reached, the mechanism by which the response is stopped is unknown
.
The ability to bypass this upper limit will allow regeneration
to be studied without prior liver damage.
Understanding how to engage de novo in regenerative mechanisms will provide a paradigm shift in adult organ regeneration and rejuvenation clinical strategies that can reduce or replace transplantation, but no such in vivo model is currently available
.

Mycobacterium leprae

 02 

Researchers at the University of Edinburgh in the United Kingdom have found that leprosy bacteria can reprogram cells to increase the size of adult livers without causing damage, fibrosis or tumors, and can also help damaged livers regenerate, thereby reducing the need
for transplantation.
In the study, researchers infected 57 armadillos with leprosy bacteria, the natural host of leprosy bacteria, and compared
their livers to those of uninfected armadillos and livers found to be infection-resistant.

A natural in vivo model of ML-infected Nine-banded Armadillo was reported for mammalian adult liver growth at the organ level without prior damage
.
Bacteria-induced partial reprogramming in the body significantly increases liver size with sustained function and structure, but no damage, fibrosis, or tumorigenesis
during the establishment phase of infection.
Defines which cell types promote the growth of this organ and indicates the number of healthy liver lobules, rather than size, hepatocyte mass, and proportional expansion
of the vascular and bile duct systems.
Evidence showing that ML has adapted dynamic partial reprogramming, regeneration, and developmental/fetal mechanisms to promote de novo hepatic organogenesis while maintaining tissue protection and tumor prevention strategies
.

Conceptual progress

 03 

Liver disease kills 2 million people each year
.
No trials using lab-grown stem cells for cirrhosis have yielded any licensed therapies
.
The failure to develop therapies for solid organ diseases using injectable stem cells suggests that alternative strategies
reflecting the complexity of organ growth and regeneration should be explored.
2D, 3D, and in vitro models have shown progress, but their clinical application in large solid organs is limited
.
In addition, current knowledge of liver regeneration in vivo comes from transient rodent injury or hepatectomy models
.

Taking advantage of the regenerative and metabolic properties of the liver, the metabolically rich liver microenvironment compensates for known defects in ML metabolism, inducing many metabolic genes
in infected livers.
Since the observed healthy liver growth in vivo is not stimulated by other bacterial species or drug treatments, liver growth appears to be ML-specific.

Maintaining a functional liver for expansion allows host cell-dependent intracellular bacteria to multiply
during the establishment phase of infection.
Given that the presence of immune cells varies, but there is no histological cell death or fibrosis, one can speculate that part of the adaptation of ML to host response involves regulating innate immune cell activity, preventing tissue damage
.

This evolutionarily improved in vivo model may advance our understanding of natural regenerative mechanisms and determine how to engage de novo to allow new organ regeneration strategies for potential clinical use, a conceptual advance with broader implications
in regenerative medicine.

Resources:

https://doi.
org/10.
1016/j.
xcrm.
2022.
100820

Note: This article is intended to introduce the progress of medical research and cannot be used as a reference
for treatment options.
If you need health guidance, please go to a regular hospital
.

Sub-forum 1

Tumor immunity "Pujiang Discussion" schedule

Sub-forum II

Tumor immunity "Matsue traceability" schedule

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