Nearly two decades have elapsed since stem cells were debuted on the new medical therapies stage with much fanfare. The first act of the highly touted show starred stem cells obtained from human embryos as magical new cell medicines with potential to remedy a panorama of chronic debilitating diseases and ailments for which no cures or even palliative treatments existed. Human embryonic stem cells (hESCs) also had the important practical attribute of proliferation properties that were suitable for future mass manufacturing. Good manufacturing potential was an important quality for enticing pharmaceutical companies to consider entering the arena of cell therapy development, much in the way that they had entered the new arena of biologics therapy development, 25 years earlier, after technologies for the mass production of biologic drugs were established. A similar confluence of drug development elements appears under way now for CAR-T cancer immunotherapy. Therapeutic effect and manufacturing capability, these are two essential elements that a new therapeutic discipline needs to attract the interest and investment of big pharma.

So far, in the case of stem cell therapy, the discipline has experienced disastrous mismatches between the ability to manufacture different types of stem cells and their respective therapeutic efficacy. These recognized, but greatly underestimated, challenges have kept the pharmaceutical industry largely on the sidelines of stem cell medicine. This state of affairs is a major impediment to progress in stem cell regenerative medicine by depriving the emerging new medical discipline the acceleration that full engagement of the pharmaceutical industry could bring.

GOOD MANUFACTURING POTENTIAL, POOR THERAPEUTIC POTENTIAL
Much to the chagrin of their promoters, very soon after hESCs took the stage, the curtain came crashing down. The fall is most often blamed on outbreaks of moral and ethical objections to the first step in the production process for hESCs. The source human embryos were destroyed as a result of the extraction of the precursor cells used to produce hESCs. Many considered this unavoidable processing step sufficiently unsavory to warrant prohibiting the production and use of hESCs for research or development of new therapies.

In reality, there were many other factors that would have brought the curtain down as well, even if the moral and ethical concerns could have been appeased. The truth of this statement is evident from the historical course of induced pluripotent stem cells (iPSCs). Similar to hESCs, iPSCs have the ability to convert into many different types of body cells. This property, called pluripotency, has been the main selling point for both hESCs and iPSCs. However, they differ in their origin in a very important manner. The production of iPSCs does not require human embryos, and therefore is free of moral and ethical concerns.

Like hESCs, iPSCs have shown potential for manufacturing success. Several biotechnology companies now market manufactured iPSCs for research purposes. Unfortunately, this manufacturing progress has not been matched with therapeutic progress or potential. Like hESCs that inspired their development, iPSCs have many biological and technical shortcomings that pretty much eliminate them from having a future substantial impact in stem cell medicine.

First and foremost, like hESCs, iPSCs are potentially very dangerous, because they form tumors when injected into the mature tissues of animals. Second, it is now recognized that these pluripotent stem cell types do not have the previously widely pronounced magical property of “being able to make every type of cell in the human body.” So far, they have proven quite restricted in their ability to produce mature human tissues as originally envisioned. Though they can be induced to convert into some types of tissue cells with greater maturity, the degree of maturation is limited to fetal cell-like properties. The fetal-like cells will have inadequacies for use in both cell therapy and drug development for disorders in children and adults. In addition to inadequacies due to immature development, mature cells produced from pluripotent stem cells are also at high risk for functional deficiencies caused by gene defects that pluripotent stem cells are known to harbor at high rates.

Finally, though less noted, even if pluripotent stem cells did not form tumors, they would still be deficient for producing long-lasting cures in children and adults. They lack an essential property required to maintain, repair, and restore mature human tissues. That property, called asymmetric self-renewal, is the unique province of another type of stem cells, adult tissue stem cells (TSCs).

GOOD THERAPEUTIC POTENTIAL, POOR MANUFACTURING POTENTIAL
Adult tissue stem cells are rare cells found in all mature tissues in children and adults. They are responsible for the continuous renewal and repair of mature tissue cells. Asymmetric self-renewal by TSCs is characterized by asymmetric stem cell divisions that produce both stem cells and committed cells simultaneously. Stem cells can divide indefinitely, but their tissue fraction remains low and constant because of the format of the asymmetric self-renewal tissue system. The committed cells produced by asymmetric stem cell divisions undergo many additional divisions to produce the mature cells of the tissue. However, all of the last cells produced in a committed lineage undergo a permanent arrest from division when they reach final maturity. When old mature cells expire, next-in-lineage maturing cells replace them. As the base cell for this cellular replenishment system, stem cells keep renewing mature tissue cells while their own number is maintained at a very low fraction of total cells.  There are many developmental and evolutionary advantages ascribed to this universal, unique property of TSCs in mammalian organs and tissues. In addition, under conditions of injury, TSCs can divide symmetrically, producing only stem cells transiently for the purpose of making new tissue units for the repair of tissue cell defects.