Adding One Gene to Cells can Regrow Hair, Cartilage, Bone and Soft Tissues

The reactivation of a gene called Lin28a, which is active in embryonic stem cells, can regrow hair and repair cartilage, bone, skin, and other soft tissues in mice.

This study comes from scientists at the Stem Cell Program at Boston Children’s Hospital who found that the Lin28a promotes tissue repair by enhancing metabolism in mitochondria, which are the energy-producing engines in cells. These data suggest that upregulation of common “housekeeping” functions might provide new ways to develop regenerative treatments.

George Q. Daley, the director of Boston Children’s Hospital Stem Cell Transplantation Program, said, “Efforts to improve wound healing and tissue repair have mostly failed, but altering metabolism provides a new strategy which we hope will prove successful.”

One of the first authors of this paper, Shyh-Chang Ng, added, “Most people would naturally think that growth factors are the major players in wound healing, but we found that the core metabolism of cells is rate-limiting in terms of tissue repair. The enhanced metabolic rate we saw when we reactivated Lin28a is typical of embryos during their rapid growth phase.”

Lin28a was first discovered in worms, but the Lin28a gene is found in all animals. It is abundantly expressed in embryonic stem cells and during early embryonic development. Stem cell scientists have even used Lin28a to help reprogram adult cells into induced pluripotent stem cells. Lin28a encodes an RNA-binding protein that regulates the translation of messenger RNAs into protein.

To express more of this protein in mice, Daley and his colleagues attached the Lin28a gene to a piece of DNA that would drive expression when the mice were fed the drug doxycycline. Ng and others noticed that one of the targets of Lin28a was a small RNA molecule called Let-7, which is known to promote aging and cell maturation. Let-7 is a member of a class of non-coding RNA molecules called micro-RNAs that bind to messenger RNAs and prevent their translation.  Let-7 is made as a larger precursor molecule that is processed to a smaller molecule that is functional.  LIN28 binds specifically to the primary and precursor forms of Let-7, and inhibits Let-7 processing.

Lin28a function

Ng said, “We were confident that Let-7 would be the mechanism, but there was something else involved.”

Let-28a is known to activate the translation of several different genes that play a role in basic energy metabolism (e.g., Pfkp, Pdha1, Idh3b, Sdha, Ndufb3, and Ndufb8), Activation of these genes enhances oxidative metabolism and promotes an embryonic bioenergetic state.

In their Lin28a transgenic mice, Daley, Ng and others noticed that Lin28a definitively enhanced the production of metabolic enzymes in mitochondria, and that these “revved up” the mitochondria so that they generated the energy needed to stimulate and grow new tissues.


“We already know that accumulated defects in mitochondria can lead to aging in many cells and tissues,” said Ng. We are showing the converse: enhancement of mitochondrial metabolism can boost tissue repair and regeneration, recapturing the remarkable repair capacity of juvenile animals. ”

Further experiments showed that bypassing Lin28a and directly activating mitochondrial metabolism with small molecules had the same effect on wound healing. This suggests that pharmaceuticals might induce regeneration and enhance tissue repair.

“Since Lin28 itself is difficult to introduce into cells, the fact that we were able to activate mitochondrial metabolism pharmacologically gives us hope,” said Ng.

Lin28a did not cause universal regeneration of all tissues. Heart tissue, for example, was poorly aided by Lin28a. Also, Lin28a induced the regeneration of severed finger tips in newborn mice, but not in adult mice.

Nevertheless, Lin28a could be a key factor in constituting a kind of healing cocktail, in combination with other embryonic factors yet to be found.

Genomic Imprinting Maintains A Reserve Pool of Blood-Forming Stem Cells

Hematopoietic stem cells or HSCs reside in the bone marrow and give rise to the wide variety of specialized blood cells that inhabit our bloodstreams. Within the bone marrow, HSCs come in two varieties: an active arm of HSCs that proliferate continually to replace our blood cells and a reserve arm that sits and quietly waits for their time to come.

New research from the Stowers Institute at Kansas City, Mo, in particular a research team led by Linheng Li, discovered a mechanism that helps maintain the balance between those HSCs kept in reserve and those on active duty.

According to Dr. Li, genomic imprinting, a process that specifically shuts off one of the two gene copies found in each mammalian cell , prevents the HSCs held in reserve from being switched to active duty prematurely.

Li explained: “Active HSCs form the daily supply line that continually replenishes worn-out blood and immune cells while the reserve pool serves as a backup system that replaces damaged active HSCs and steps in during times of increased need. In order to maintain a long-term strategic reserve of hematopoietic stem cells that lasts a lifetime it is very important to ensure that the back-up crew isn’t mobilized all at once. Genomic imprinting provides an additional layer of regulation that does just that.”

Sexual reproduction produces progeny that have once set of chromosomes from the mother and one set of chromosomes from the father. The vast majority of genes are expressed from both sets of chromosomes. However, in placental mammals and marsupial mammals a small subset of genes are imprinted, which means that they receive a mark during the development of eggs and sperm and these marks shut down expression of those genes in either the sperm pronucleus or the egg pronucleus. Therefore, after the fusion of the sperm and the egg and the eventual fusion of the egg and sperm pronuclei, these imprinted genes are only expressed from one copy of genes. Some are only expressed from the paternal chromosomes and others are only expressed from the maternal chromosome. Imprinting is essential for normal development in mammals.

The importance of genetic imprinting is shown if an egg loses its pronucleus and is then fertilized by two sperms. The resulting zygote has two copies of paternal chromosomes and no copies of the maternal chromosomes. Such an embryo is called an andogenote, and the embryo fails to form but the placenta overgrows. If this occurs during human development, it can lead to a so-called “molar pregnancy” or “hydatiform mole.” This fast growing placental tissue can become cancerous and lead to uterine cancer. For that reason, molar pregnancies are usually dealt with expeditiously.

However, if the sperm that fertilizes the egg is devoid of a pronucleus, and the egg pronucleus duplicates, then the resulting zygotes can two copies of the maternal chromosomes, and this entity is known as a gynogenote, and it develops with a poorly formed placenta that dies early in development.

In previous experiments in mice, Li and his colleagues indicated that the expression of several imprinted genes changes as HSCs transition from quiescent reserve cells to multi-lineage progenitor cells.

In their current study, Li and other Stowers Institute researchers examined a differentially imprinted control region, which drives the reciprocal expression of a gene called H19 from the maternal chromosome and IGF2 (insulin-like growth factor-2) from the paternal chromosome.

The first author of this study, Aparna Venkatraman developed a mouse model that allowed her to specifically delete the imprinted copy from the maternal chromosome. Thus, in these mice, H19, which restricts growth, was no longer active and Igf2,, which promotes cell division, was now active from the paternal and the maternal chromosome. To access the effect of this loss of imprinting on the maintenance of HSCs, Venkatraman examined the numbers of quiescent HSCs and active HSCs. in mouse bone marrow.

Venkatraman explained: “A large number of quiescent HSCs was activated simultaneously when the epigenetic control provided by genomic imprinting was removed. It created a wave of activated stem cells that moved through different maturation stages.”

She followed this experiment with a closer look at the Igf2 gene. Misregulation of Igf2 leads to overgrowth syndromes such as Beckwith-Wiedmann Syndrome. It exerts its growth promoting effects through the Igf1 receptor, which induces an intracellular signaling cascade that stimulates cell proliferation.

IGF signaling pathway
IGF signaling pathway

The expression of the Igf1 receptor itself is regulated by H19, which encodes a regulatory microRNA (miR-675) that represses translation of the Igf1 receptor gene and therefore prevents production of Igf1 receptor protein. Venkatraman explained that once the “imprinting block is lifted, the Igf2-Igf1r signaling pathway is activated.” Venkatraman continued: “The resulting growth signal triggers the inappropriate activation and proliferation of quiescent HSCs, which eventually leads to the premature exhaustion of the reserve [HSC] pool.”

Interestingly, the roundworm, Caenorhabditis elegans, provided the first clues that diminished insulin/IGF signaling can increase lifespan and delay aging. Li again: “Here the IGF pathway is conserved by subject to imprinting, which inhibits its activation in quiescent reserve stem cells. This ensures the long-term maintenance of the blood system, which in turn supports the longevity of the host.”