Researchers from the extremely prolific Salk Institute laboratory of Juan Carlos Izpisua Belmonte have designed a new method for generating stem cells from mature, adult cells that has the potential to boost laboratory production of stem cells. This technique could overcome an important barrier to regenerative medical therapies that would replace damaged or unhealthy tissues.
This new stem cell production technique allows for the unlimited production of stem cells and stem cell derivatives and also considerably reduces the time it takes to produce these cells; instead of taking two months, Juan Carlos’ lab can make them in two weeks.
Ignacio Sancho-Martinez, one of the first authors of this paper, said, “One of the barriers that needs to be overcome before stem cell therapies can be widely adopted is the difficulty of producing enough cells quickly enough for acute clinical application.”
Sancho-Martinez and his colleagues in the Belmonte laboratory published this new method in the journal Nature Methods.
Stem cells are important for regenerative medicine because of their pluripotency. Pluripotency refers to the ability of a stem cell to differentiate into any cell in the adult human body. Pluripotent stem cells for research and clinical uses are derived from one of two sources; embryos or from adult cells that have been reprogrammed to be pluripotent.
Pluripotent stem cells from embryos – embryonic stem cells (ESCs) – have the disadvantage of being rejected by the immune system when they are placed in the body of a patient. Therefore, scientists have attempted to develop clinical therapies with pluripotent stem cells made by reprogramming adult cells – induced pluripotent stem cells or iPSCs. Because these cells are made from the patient’s own cells, they should possess the same set of surface proteins as the patient. Therefore the patient’s immune should not recognize them as foreign.
Unfortunately, there are drawbacks to iPSCs. The method by which iPSCs are made from adult cells is rather inefficient and is also time-consuming and labor-intensive. Furthermore, once the iPSCs are made, they must be differentiated into the desired cell type. Differentiation is rarely 100% efficient and if the differentiated cells cannot be effectively isolated from the incompletely differentiated cells, they can cause tumors upon implantation.
To circumvent these problems, scientists have tried to reprogram cells to something other than a pluripotent state. Reprogramming adult cells into a “multipotent” state rather than a pluripotent state is potentially easier, faster, and does not carry the risk of tumor formation. Unlike pluripotent cells, which can become any adult cell type, multipotent cells can only differentiate into a small subset of the possible adult cells. The reprogramming of adult cells into multipotent progenitor cells is called “direct lineage conversion.”
While direct lineage conversion works rather well, it is a one-for-one conversion; one skin cell is converted into one muscle cell, and so on. This makes the technique inherently unproductive, since regenerative medical strategies will require large quantities of cells. Thus, Izpisua Belmonte’s laboratory examined ways to increase the output from direct lineage conversion.
Leo Kurian, a Salk Institute post-doctoral researcher, and one of the first co-authors on this paper, explained it this way: “Beyond the obvious issue of safety, the biggest consideration when thinking about stem cells for clinical use is productivity.”
To this end, this Salk Institute team invented a new technique that they called “indirect lineage conversion,” or ILC. During ILC, somatic cells are pushed back to an earlier stage of development that is suitable for the specification of multipotent progenitor cells. Because these multipotent progenitor cells have the capacity to divide, they can be expanded to greater numbers.
ILC has the potential to produce multiple lineages once adult cells are transferred to the a special environment designed by Belmonte’s lab. Most importantly, ILC saves time and also reduces the risk of tumor formation, since the adult cells are reprogrammed to become particular lineage progenitors rather than iPSCs. In the words of Sancho-Martinez, “We don’t push then to zero, we just push them back a bit.”
See Leo Kurian, et al., “Conversion of human fibroblasts to angioblast-like progenitor cells.” Nature Methods 2012; DOI:10.1038/nmeth.2255.