The Niche

Do induced pluripotent stem cells arise from skin stem cells?

In June, widely publicized work from three labs showed that specialized cells could be reprogrammed after transfection with four genes. In this correspondence, James Trosko suggests an alternative explanation, that the reprogrammed cells identified by groups led by Shinya Yamanaka, Rudolf Jaenisch, and Konrad Hochedlinger and Kathrin Plath could in fact be skin stem cells reprogrammed to an embryonic state.

Another thread discusses how reprogramming work alters perceptions of whether dedifferentiation is active or passive, and adds insight from in silico modeling.

Below is the email correspondence between the scientists:

Dr. Trosko’s suggestion that identified cells are stem cells already residing in skin

June 24, 2007

Dear Drs. Jaenisch & Yamanaka:

After reading the summary report[ "Simple switch turns cells embryonic" by

David Cyranoski in Nature , 6th, 2007] , which, if I assume to accurately

describe your research results in the 2 Nature and 1 Cell Stem Cell

papers, I was led to think that there might be an alternative explanation

for your results.

To be succinct, since all adult tissues have “adult stem cells”, which

express the Oct-4 gene [ see my paper: Tai, M.-H., et al., " Oct-4

expression in adult human stem cells: evidence in support of the stem cell

theory of carcinogenesis." Carcinogenesis 26: 495-502, 2005]( see

attached) and since it seems that stem cells express drug resistance genes,

such as ABCG-2, the cells that were selected were the natural adult stem

cells and not those transfected with your drug selection markers. In

essence, I believe the cells did not become “re-programmed” because of the

transfection with Oct-4 and nanog, but were already expressing those genes

as an adult stem cell residing in the skin. One must surely know that of all

the organs of the body, the skin has adult stem cells ( see our paper with

both human and canine normal skin showing a few adult Oct-4 expressing

cells). Any reprogramming that might have taken place would have been from

an adult skin stem cell to an embryonic-like state, not from an adult

somatic differentiated skin fibroblast.

I would like to hear what your view of this interpretation is.

I await your reply,

Respectfully submitted,

James E. Trosko, Ph.D.

on Sabbatical Leave

Dept. of Oncology

ARNAS -Civico

Piazzale N. Leotta 2

90127 Palermo, Italy


Home Institution

Dept. of Pediatrics and Human Development

College of Human Medicine

Michigan State University

East Lansing, Michigan 48824

Shinya Yamanaka’s reply

June 24, 2007

Dear Dr. James E. Trosko

Thank you very much for your interest in our work.

I agree that the origin of iPS cells cell might be tissue stem cells

co-existing in fibroblast cultures. I discussed this possibility in both the

Cell and Nature papers.

However, I disagree with your explanation that we are simply selecting

tissue stem cells that naturally express Oct4 and Nanog. The reasons are

summarized below:

1. In the Nature paper, we used GFP knocked into the Nanog locus to select

iPS cells. Therefore, the drug resistant issue by transporters does not

apply to our work.

2. Without introducing the four factors, we did not obtain any iPS cells.

3. All the iPS cell clones we have analyzed have multiple copies of the

retroviruses of the four factors.

I hope these are clear enough.

Best wishes,

Shinya Yamanaka

Rudolf Jaenisch’s reply

July 3, 2007

Dear Dr. Trosko,

This is in response to your concerns regarding the nature of in vitro reprogrammed iPS cells. Whether somatic stem cells are easier to repgrogram than differentiated cell is an interesting issue that needs to be addressed in future experiments. However, as Shinya Yamanaka pointed out in his response, because all iPS cells carry multiple copies of the Oct4 virus, it seems to be unlikely that the reprogramming procedure just selected “normal adult stem cells”. This result rather is consistent with the conclusion that Oct4 (and the other factors) need to be expressed at high levels in the fibroblasts.

With best regards,

Rudolf Jaenisch

Konrad Hochedliner’s reply

July 3, 2007

Dear Dr. Trosko,

Thank you for your comments on our articles. I agree with Dr.

Jaenisch’s and Dr. Yamanaka’s views. In support of their arguments, our

results with a doxycycline inducible Oct4 allele (Fig. 3B of our Cell

Stem Cell paper) are in agreement with the (previous) notion that

exogenous Oct4 expression is absolutely required to obtain iPS cells.

Best regards,

Konrad Hochedlinger

Dr. Trosko’s responses

July 4, 2007

Dear Dr. Jaenisch:

Thank you for your response. While I agree that the explanation of Dr. Yamanaka seems consistent, it certainly does not “disprove” the issue I raised. I agree that future experiments must be done to show that a normal, Oct-4 adult stem cell can be rescued from normal tissue, using the procedures that do not involve an exogenous set of embryonic stem cell-determining genes and can be functional in the manner demonstrated in the published experiments.

I, also, agree that the issue of whether somatic or adult stem cells are easier to “re-program” than differentiated cells is an important issue , but that, again, must await the resolution of the issue I raised, since an adult stem cell may need little “re-programming” aside from the committed genes it contains for its specific multi-potency.

Most sincerely,

James E. Trosko, Ph.D.

July 4th, 2007

Dear Dr. Hochedlinger:

As I have indicated in my response to Dr. Jaensch, I agree with all of your explanations as being in agreement with the observations. I still am not sure it explains the possibility that the multiple copies of Oct-4 transfected an adult stem cell with Oct-4 already expressed.( Adult stem cells do exists in somatic tissues, such as the skin, and they express Oct-4 and probably drug resistance genes.).

It will be very interesting to see if a normal adult skin stem cell, with just its own set of stemness genes ( Oct-4, Nanog, etc) could act like an “embryonic-like” stem cell. That experiment has to be performed.

Thank you for responding to my query.

Most sincerely,

James E. Trosko, Ph.D.


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