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As I understand it, induced pluripotent stem cells (iPSC's) can be made using the following (grossly oversimplified) steps:

  1. Take some skin cells (fibroblasts) from the host
  2. Introduce the transcription factors Oct3/4, Sox2, Nanog, and Lin28 using retroviruses to reprogram them into pluripotent stem cells
  3. Reintroduce the reprogrammed cells into the host

I do not understand why steps 1 and 3 are needed, and why the retroviruses can't be introduced directly into the target area to create the iPSC's in vivo. My guesses are:

  • The culture conditions within an animal body are not sufficient for reprogramming or differentiation (low methylation?)
  • The retroviruses would die off before they could deliver the transcription factors uniformly enough or in large enough numbers for any meaningful regeneration to occur, either due to the immune system or simply because they are not self-replicating
  • Because the cells would not be transfected at exactly the same time, and would already be surrounded by many differentiated cells, a newly created transfected cell may immediately differentiate based on its surroundings, causing no noticeable difference compared to the cell being made through un-transfected cell division
  • I am misunderstanding how reprogrammed cells act, and all reprogrammed cells form a blastocyst from which the actual useful stem cells are harvested
  • Using the retroviruses directly could cause organs cells to become transfected and differentiate in unexpected ways, harming the host

I am not a biologist so please feel free to point out any and all misunderstandings I may have shown. The transcription factors mentioned are the ones which work on humans according to what I read, but this question is not about humans specifically.

Edit: this question appeared in the Related tab after I posted my question, but wouldn't immunosuppressants or more infectious/illusive vectors circumvent the immune system issue?

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    $\begingroup$ I don't know which specific barriers are the most important, but certainly it is not simply trivial to say "immunosuppressants would circumvent the immune system issue". Immune suppression is a terrible, terrible condition to induce. It's done when the alternative is death in short order. That doesn't mean that some people don't live long, productive lives on immune suppressants after e.g. organ transplants, but it's not something you'd choose for anyone that didn't absolutely need it. $\endgroup$
    – Bryan Krause
    Oct 24, 2022 at 19:28
  • $\begingroup$ But assuming it was induced temporarily (long enough for the targeted tissues to have the transcription factors delivered) in an isolated environment, would it still be effective? I'm not trying to imply it's something to try on a whim any more than if I had said "radiation would circumvent the issue of cancer cell replication", I'm just listing possibilities (not solutions) based on my limited understanding. $\endgroup$
    – Gumpf
    Oct 24, 2022 at 19:43

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Pluripotent stem cells, regardless if they’re of embryonic or iPSC origin, will form a very nasty (and often very deadly) form of cancer called teratoma when present in adult tissue (Wesselschmidt 2011, Choi 2015).

I read from your question that your goal is to regenerate tissue. Although iPSCs were a breakthrough in understanding stem cell biology in general, their use in regenerative medicine is still very challenging, since their embryonic-like state is too multipotent and dangerous. Even adult stem cells (like mesenchymal stem cells, hematopoietic stem cells) are undergoing vast changes until they reach their terminal state. And even they need specific signals to develop into the right tissue type. Even when transplanting stem cell grown organs, one has to make sure that every cell is terminally differentiated, otherwise your new liver might grow something random like a set of teeth. People try to circumvent the pluripotent state to solve this problem (Pushp 2021).

Together, you were right with your last point: even if the direct retroviral transfection would work, there won‘t be directed tissue regeneration but random organ growth.

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