Gum Nerve Cells Become Tooth-Specific Mesenchymal Stem Cells


Stem cells self-renew and also produce progeny that differentiate into more mature cell types. The neurons and glia that compose nervous systems are examples of mature cells and these cells can be produced from embryonic stem cells, induced pluripotent stem cells, or neural stem cells. However, the reverse does not occur during development; more mature cells do not de-differentiate into less mature cells types. Development tends to be a one-direction event.

However, researchers have now discovered that inside teeth, nervous system cells can transform back into stem cells. This unexpected source of stem cells potentially offers stem cell scientists a new starting point from which to grow human tissues for therapeutic or research purposes without using embryos.

“More than just applications within dentistry, this finding can have very broad implications,” says developmental biologist Igor Adameyko of the Karolinska Institute in Stockholm, who led this new work. “These stem cells could be used for regenerating cartilage and bone as well.”

The soft “tooth pulp” in the center of teeth has been known to contain a small population of tooth-specific mesenchymal stem cells, which can typically differentiate into tooth-specific structures, bones, and cartilage. However, no one has conclusively determined where these stem cells came from. Adameyko hypothesized that if he could trace their developmental lineage, he should be able to recapitulate their development in the laboratory. This might offer new ways of growing stem cells for tissue regeneration.

Adameyko and his and colleagues had already studied glial cells, which are nervous system cells that surround neurons and support them. Several of the nerves that wind through the mouth and gums help transmit pain signals from the teeth to the brain are associated with glial cells.

Adameyko and others used fluorescent labels to mark the glial cells in the gum. When the gum-specific glial cells were observed over time, some of these cells migrated away from neurons in the gums into teeth, where they differentiated into mesenchymal stem cells. These same cells then matured into tooth cells. This work was reported in the journal Nature.

a–c, Incisor traced for 3 days from adult PLP-CreERT2/R26YFP mouse. Note protein gene product 9.5 (PGP9.5)+ nerve fibres (a). b, c, Magnified areas from a. d, e, Incisor traced for 30 days from adult PLP-CreERT2/R26YFP mouse. Note collagen IV+ blood vessels (d). e, YFP+ odontoblasts and adjacent pulp cells. f, Incisor traced for 30 days from Sox10-CreERT2/R26YFP mouse. g–k, Incisor traced for 40 days from PLP-CreERT2/R26Confetti incisor. h–j, Magnified areas from g. Arrow in h indicates a cluster of odontoblasts; arrow in j points at CFP+ and RFP+ cells in proximity to a cervical loop at the base of CFP+ and RFP+ streams shown in g and i. k, Streams of CFP+ and RFP+ pulp cells next to i and j. l, m, Incisor traced for 40 days from PLP-CreERT2/R26Confetti mouse with YFP+ and RFP+ pulp cells adjacent to clusters of odontoblasts with corresponding colours. m, Magnified region from l. n, Stream of pulp cells (arrows) in proximity to the cervical loop; yellow and red isosurfaces mark YFP+ and RFP+ cells. o, p, Progenies of individual MSCs intermingle with neighbouring clones in pulp (o) and odontoblast layer (p), projections of confocal stacks. q, r, Clonal organization of mesenchymal compartment in adult incisor. a–n, Dotted line, enamel organ and mineralized matrix. Scale bars, 100 µm (a, d, f, g, k, l); 50 µm (b, c, e, m–p). CL1 and CL2 indicate labial and lingual aspects of cervical loop. d.p.i., days post-injection. s, Incidence of mesenchymal clones depending on fraction of odontoblasts within the clone. t–v, Proximity of dental MSCs (dMSCs) to cervical loop (CL) correlates with clonal size and proportion of odontoblasts in clone.
a–c, Incisor traced for 3 days from adult PLP-CreERT2/R26YFP mouse. Note protein gene product 9.5 (PGP9.5)+ nerve fibres (a). b, c, Magnified areas from a. d, e, Incisor traced for 30 days from adult PLP-CreERT2/R26YFP mouse. Note collagen IV+ blood vessels (d). e, YFP+ odontoblasts and adjacent pulp cells. f, Incisor traced for 30 days from Sox10-CreERT2/R26YFP mouse. g–k, Incisor traced for 40 days from PLP-CreERT2/R26Confetti incisor. h–j, Magnified areas from g. Arrow in h indicates a cluster of odontoblasts; arrow in j points at CFP+ and RFP+ cells in proximity to a cervical loop at the base of CFP+ and RFP+ streams shown in g and i. k, Streams of CFP+ and RFP+ pulp cells next to i and j. l, m, Incisor traced for 40 days from PLP-CreERT2/R26Confetti mouse with YFP+ and RFP+ pulp cells adjacent to clusters of odontoblasts with corresponding colours. m, Magnified region from l. n, Stream of pulp cells (arrows) in proximity to the cervical loop; yellow and red isosurfaces mark YFP+ and RFP+ cells. o, p, Progenies of individual MSCs intermingle with neighbouring clones in pulp (o) and odontoblast layer (p), projections of confocal stacks. q, r, Clonal organization of mesenchymal compartment in adult incisor. a–n, Dotted line, enamel organ and mineralized matrix. Scale bars, 100 µm (a, d, f, g, k, l); 50 µm (b, c, e, m–p). CL1 and CL2 indicate labial and lingual aspects of cervical loop. d.p.i., days post-injection. s, Incidence of mesenchymal clones depending on fraction of odontoblasts within the clone. t–v, Proximity of dental MSCs (dMSCs) to cervical loop (CL) correlates with clonal size and proportion of odontoblasts in clone.

Before this experiment, it was generally believed that nervous system cells were unable to de-differentiate or revert back to a flexible stem cell state. Therefore, Adameyko said that it was very surprising to see such a process in action. He continued: “Many people in the community were convinced … that one cell type couldn’t switch to the other. But what we found is that the glial cells still very much maintain the capacity” to become stem cells. If stem cell researchers and physicians could master those chemical cues in the teeth pulp that signals glial cells to transform into mesenchymal stem cells, they could generate a new way to grow and make stem cells in the lab.

“This is really exciting because it contradicts what the field had thought in terms of the origin of mesenchymal stem cells,” says developmental biologist Ophir Klein of the University of California, San Francisco, who was not involved in the new work. But it’s also just the first step in understanding the interplay between the different cell populations in the body, he adds. “Before we really put the nail in the coffin in terms of where mesenchymal stem cells are from, it’s important to confirm these findings with other techniques.” If that confirmation comes, a new source of stem cells for researchers will be invaluable, he says.

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Identifying Barriers to Cell Reprogramming


A new study from the laboratory of Miguel Ramalho-Santos, associate professor of obstetrics, gynecology and reproductive sciences at the University of California, San Francisco (UCSF), might lead to a faster way to derive stem cells that can be used for regenerative therapies.

Induced pluripotent stem cells or iPSCs, which are made from adult cells by means of genetic engineering and cell culture techniques, behave much like embryonic stem cells. These adult cell-derived stem cells are pluripotent and can be differentiated into heart, liver, nerve and muscle cells. This present work by Ramalho-Santos and his colleagues builds upon the reprogramming protocols that have been developed to de-differentiate mature adults cells into iPSCs.

Ramalho-Santos and his co-workers have been interested in understanding the reprogramming process more completely in order to increase the efficiency and safety of this process. In particular, the Ramalho-Santos laboratory has been examining the cellular barriers that prevent adult cells from being reprogrammed in order to circumvent them and increase the efficiency of stem-cell production. In this present work, Ramalho-Santos’ group identified many of these cellular barriers to reprogramming.

“Our new work has important implications for both regenerative medicine and cancer research,” said Ramalho-Santos, who is also a member of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF.

In 2012, Shinya Yamanaka from Kyoto University won the Nobel Prize in Physiology or Medicine for his discovery of iPSCs. Yamanaka discovered ways to turn back the clock on adult cells, but the protocol that he developed and others have used for years is inefficient, slow, and tedious. The percentage of adult cells successfully converted to iPS cells is usually rather low, and the resultant cells often retain traces of their earlier lives as mature, fully-differentiated cells.

To make iPSCs, researchers force the expression of pluripotency-inducing genes in adult cells. These four genes (Oct4, Klf4, Sox2, cMyc) have become known as the so-called “Yamanaka factors” and they work to turn back the clock on cellular maturation. However, as Ramalho-Santos explained: “From the time of the discovery of iPS cells, it was appreciated that the specialized cells from which they are derived are not a blank slate. They express their own genes that may resist or counter reprogramming.”

So what are those barriers? Ramalho-Santos continued: “Now, by genetically removing multiple barriers to reprogramming, we have found that the efficiency of generation of iPS cells can be greatly increased.” This discovery will contribute to accelerating the production of safe and efficient iPSCs and other types of other reprogrammed cells, according to Ramalho-Santos.

Instead of identifying individual genes that act as barriers to reprogramming, Ramalho-Santos and others discovered that sets of genes acted in combination to establish barriers to reprogramming. “At practically every level of a cell’s functions there are genes that act in an intricately coordinated fashion to antagonize reprogramming,” Ramalho-Santos explained. These existing mechanisms probably help mature, adult cells maintain their identities and functional roles. Ramalho-Santos explained it this way: “Much like the Red Queen running constantly to remain in the same place in Lewis Carroll’s ‘Through the Looking-Glass,’ adult cells appear to put a lot of effort into remaining in the same state.” Ramalho-Santos also added that apart from maintaining the integrity of our adult tissues, the barrier genes probably serve important roles in other diseases, including in the prevention of certain cancers

To identify these barriers, Ramalho-Santos and his team had to employ cutting-edge genetic, cellular and bioinformatics technologies. They collaborated with other UCSF labs headed by Jun Song, assistant professor of epidemiology and biostatistics, and Michael McManus, associate professor of microbiology and immunology.

They conducted genome-wide RNAi screens that revealed known and novel barriers to human cell reprogramming. Of these, a protein called ADAM29 antagonizes reprogramming as does clathrin-mediated endocytosis, which antagonizes reprogramming by enhancing TGF-β signaling. Also it became apparent that different barrier pathways have a combined effect on reprogramming efficiency. Additionally, genes involved in transcription, chromatin regulation, ubiquitination, dephosphorylation, vesicular transport, and cell adhesion also act as barriers to reprogramming.

Barriers to reprogramming

The hopes are that this knowledge will produce iPSCs faster that are safer to use and differentiate more completely.

Gene Inhibitor Plus Fish Fibrin Restore Nerve Function Lost After a Spinal Cord Injury


Scientists at UC Irvine’s Reeve-Irvine Research Center have discovered that injections of salmon fibrin injections into the injured spinal cord plus injections of a gene inhibitor into the brain restored voluntary motor function impaired by spinal cord injury.

Gail Lewandowski and Oswald Steward, director of the Reeve-Irvine Research Center at UCI, examined rodents that had received spinal cord injuries.  They were able to heal the damage by developmentally turning back the clock in a molecular pathway that is critical to the formation of the corticospinal nerve tract, and by providing a scaffold for the growing neurons so that the axons of these growing neurons could grow and make the necessary connections with other cells.  Their research was published in the July 23 issue of The Journal of Neuroscience.

The work of Steward and Lewandowski is an extension of previous research at UC Irvine from 2010.  Steward and his colleagues discovered that the axon of neurons grow quite well once an enzyme called PTEN is removed from the cells.  PTEN is short for “phosphatase and tensin homolog,” and it removes phosphate groups from specific proteins and lipids.  In doing so, PTEN signals to cells to stop dividing and it can also direct cells to undergo programmed cell death (a kind of self-destruct program).  PTEN also prevents damaged tissues from regenerating sometimes, because it is a protein that puts the brakes of cell division.  Mutations in PTEN are common in certain cancers, but the down-regulation of PTEN is required for severed axons to re-form, extend, migrate to their original site, and form new connections with their target cells.

PTEN function

 

After two years, team from U.C. Irvine discovered that injections of salmon fibrin into the damaged spinal cord or rats filled cavities at the injury site and provided the axons with a scaffolding upon which they could grow, reconnect and facilitate recovery. Fibrin produced by the blood system when the blood vessels are breached and it is a fibrous, insoluble protein produced by the blood clotting process.  Surgeons even use it as a kind of surgical glue.

“This is a major next step in our effort to identify treatments that restore functional losses suffered by those with spinal cord injury,” said Steward, professor of anatomy & neurobiology and director of the Reeve-Irvine Research Center. “Paralysis and loss of function from spinal cord injury has been considered irreversible, but our discovery points the way toward a potential therapy to induce regeneration of nerve connections.”

In their study, Steward and Lewandowski subjected rats to spinal cord injuries, and then assessed their defects.  Because these were upper back injuries, the rats all showed impaired forelimb (hand) movement.  Steward and Lewandowski then treated these animals with a combination of salmon fibrin at the site of injury and a modified virus that made a molecule that inhibited PTEN.  These viruses were genetically engineered adenovirus-associated viruses encoded a small RNA that inhibited translation of the PTEN gene (AAVshPTEN).  This greatly decreased the levels of PTEN protein in the neurons.  Other rodents received control treatments of only AAVshPTEN and no salmon fibrin.

The results were remarkable.  Those rats that received the PTEN inhibitor alone showed no improvement in their forelimb function, but those animals who were given AAVshPTEN plus the salmon fibrin recovered forelimb use (at least reaching and grasping).

“The data suggest that the combination of PTEN deletion and salmon fibrin injection into the lesion can significantly enhance motor skills by enabling regenerative growth of corticospinal tract axons,” Steward said.

Corticospinal Nerve tract

Statistics compiled by the Christopher & Dana Reeve Foundation suggests that approximately 2 percent of Americans have some form of paralysis that is the result of a spinal cord injury.  Spinal cord injuries break connections between nerves and muscles or nerves and other nerves.  Even injuries the size of a grape can cause complete loss of function below the level of the injury.  Injuries to the neck can cause paralysis of the arms and legs, an absence of sensation below the shoulders, bladder and bowel incontinence, sexual dysfunction, and secondary health risks such as susceptibility to urinary tract infections, pressure sores and blood clots due to an inability to move one’s legs.

Steward said the next objective is to learn how long after injury this combination treatment can be effectively administered. “It would be a huge step if it could be delivered in the chronic period weeks and months after an injury, but we need to determine this before we can engage in clinical trials,” he said.

Human Umbilical Cord Mesenchymal Stem Cells Form Prostate Gland Tissues


Repairing the prostate gland is an important goal in regenerative medicine. However, finding the right cell for the job has proven to be a slow and tedious search.

To that end, Wei-Qiang Gao and his colleagues from Shanghai Jiao Tong University in Shanghai, China, used mesenchymal stem cells from human umbilical cord (hUC-MSCs) to test the ability of these cells to differentiate into prostate-specific cells. They combined hUC-MSCs with rat urogenital sinus stromal cells (rUGSSs) and then transplanted these cells into the renal capsule of BLB/c nude mice for two months. Cells tend to grow very well under the kidney capsule because this particular microenvironment has a very rich blood supply. Also the rUGSSs provide soluble, secreted factors that induce the hUC-MSCs to differentiate into prostate-specific cells.

After removing the implanted tissue, analyses of the implanted cells showed that the hUC-MSCs differentiated into prostate epithelial-like cells. This was confirmed by the presence of prostate specific antigen on the surfaces of these hUC-MSCs. Prostate specific antigen is only found on prostate cells, which is the reason why this protein is such a good indicator of prostate cancer. Also, the hUC-MSCs formed prostatic glandular structures that had the same cellular architecture as a normal prostate (see figure F below). Additionally, the human origin of the hUC-MSCs was further confirmed by the detection of a protein called human nuclear antigen, which is specific to human cells.

Human UC-MSCs combined with rUGSSs can generate prostate glands. Mice were sacrificed 2 months after co-transplantation surgery, and the kidneys from the cell implanted nude mice were collected. (A) Graft initiated with hUC-MSCs alone and (B) rUGSSs alone were used as negative control, respectively. (C) Graft derived with hUC-MSCs and rUGSSs. (D–F) Histological analyses of the sections of the graft stained for haematoxylin and eosin (H&E). (D) Note that while hUC-MSCs alone and (E) rUGSSs single cell type transplantation fail to regenerate prostate glandular structures. (F) co-transplantation of hUC-MSCs and rUGSSs gives rise to prostate glandular structures. Scale bar 50 mm.
Human UC-MSCs combined with rUGSSs can generate prostate glands. Mice were sacrificed 2 months after co-transplantation surgery, and the kidneys from the cell implanted nude mice were collected. (A) Graft initiated with hUC-MSCs alone and (B) rUGSSs alone were used as negative control, respectively. (C) Graft derived with hUC-MSCs and rUGSSs. (D–F) Histological analyses of the sections of the graft stained for haematoxylin and eosin (H&E). (D) Note that while hUC-MSCs alone and (E) rUGSSs single cell type transplantation fail to regenerate prostate glandular structures. (F) co-transplantation of hUC-MSCs and rUGSSs gives rise to prostate glandular structures. Scale bar 50 mm.

This interesting paper shows that hUC-MSCs can differentiate into epithelial-like cells that are normally derived from embryonic endodermal tissue. This implies that MSCs from umbilical cord can be used to repair not only prostate glands, but also other endodermally-derived tissues.

Ovarian Surface Stem Cell Population Identified in Mice


Approximately once a month, pre-menopausal women undergo ovulation. During ovulation, a mature graafian follicle is ejected from a rupture in the surface of the ovary. How does the ovary repair itself each month? Many have suspected that the ovary contains its own resident stem cell population that divides and heals the ovary after each ovulation. However, demonstrating the presence of this stem cell population and isolating the ovarian stem cells responsible for this feat have proven difficult.

Now, Nick Barker and colleagues from the University of Edinburgh have identified a cell surface protein called a “Leucine-rich-repeat-containing G protein coupled receptor 5” (LGR5) that is expressed on the surfaces of cells in the ovary surface layer. These LGR5-expressing cells seem to be the stem cell population that contributes to the ovary and oviduct covering during the formation of these organs, and then persist to repair and maintain the ovary surface layer in adults.

LGR5 is also expressed in the cells that cover several other organs. Experiments in mice have shown that LGR5+ cells are in the developing ovary from embryonic day 13.5 onwards. These LGR5-expressing cells are first detected in the ovary surface and lower layers, but later only in the surface of the ovaries of newborn mice. In adult ovaries, LGR5-expressing cells are found only in the layer of cells at the ovary surface, and in the cells that cover the far reaches of the oviduct, and in the cells that line the mesovarium ligament. These LGR5+ cells are found throughout the ovary surface, but they are most prominent in ovulating regions where the ovary surface ruptures. Barker and others also showed that in undamaged regions of the ovary, only a small proportion of dividing cells were LGR5+, but in ovaries that suffered ovulation-induced damage, cycling LGR5+ cells comprised a higher proportion (~50%) of the total percentage of ovary surface cells. These observations do not prove, but are wholly consistent with LGR5-expressing cells playing a seminal role in ovary tissue repair.

Lineage studies with marked cells in embryonic and fetal mice showed that the LGR5+ cells present during ovary development contributed to adult LGR5+ cells that are part of the ovary covering. These lineage studies show that the embryonic and fetal LGR5+ cells are the source of adult stem cells that maintain the ovary surface.

Lineage studies in adult females showed that those cells closer to damaged areas of the ovary underwent more cell divisions. Also, the marked cells on the ovary surface were not only capable of self-renewal, but they could also differentiate into more than one cell type (epithelia of the mesovarian ligament and oviduct/fimbria); this is a key characteristic that defines a stem cell population.

This Barker’s study not only more precisely maps the location of the ovarian stem cell population, but it also suggests that this stem cell population might be the source of ovarian cancers. LGR5-expressing cells might be the source of malignancies of the reproductive tract, which makes these cells important from a clinical perspective. With respect to harvesting these cells and exploiting them for regenerative strategies, it is simply too early at this point to know if this is a realistic possibility, but perhaps this will be the next phase of Barker’s very interesting research.

Making Better Induced Pluripotent Stem Cells


On July 2nd of this year, a paper appeared in the journal Nature that performed complete genomic analyses of embryonic stem cells derived from embryos or cloned embryos, and induced pluripotent stem cells (iPSCs), which are made from reprogrammed adult cells.  They found that both embryonic stem cells made from cloned embryos and iPSCs derived from the same types of adult cells contained comparable numbers of newly introduced mutations.  However, when it came to the epigenetic modification of the genome (the small chemical tags attached to specific bases of DNA that gives the cell hints as to which genes to turn off), the epigenetic pattern of the embryonic stem cells made from cloned embryos more closely resembled that from embryonic stem cells.  The iPSCs still had some similarities with the adult cells from which they were derived whereas the embryonic stem cells made from cloned embryos were more completely reprogrammed.  From this the authors claimed that making embryonic stem cells by means of cloning is ideal for cell replacement therapies.

There is a big problem with this conclusion:  This was tried in animals and it did not work because of immunological rejection of the products from the stem cells.  For more information on this, see my book, The Stem Cell Epistles, chapter 18.

Despite this “bad news” for iPSCs, two recent papers have actually provided some good news for stem cells that can heal without destroying embryos.  The first paper comes from Timothy Nelson’s laboratory at the Mayo Clinic in Rochester, Minnesota.  Differentiation of iPSCs is, in some cases, rather efficient and the isolation procedures fail to effectively isolate the differentiated cells from potentially tumor-causing cells.  However, in other cases, the differentiation is inefficient and the isolation procedures are also rather poor, which leaves a large enough population of undifferentiated tumor-causing cells.

Nelson’ group has discovered that treating iPSCs and their derivatives with anti-cancer drugs like etoposide (a topoisomerase II inhibitor for those who are interested) increases engraftment efficiency and decreases the incidence of tumors.  My only problem with Nelson’s paper is that he and his colleagues used lentiviral vectors to make their iPSCs.  These vectors tend to produce iPSCs that are rather good at causing tumors.  I would have rather that he tried making iPSCs with other methods that do not leave permanent transgenes in the cells.  Nelson and his group transplanted their iPSC-derived cells into the hearts of mice where they could use high-resolution imaging to determine the number of cells that integrated into the heart and the presence of cell masses that were indicative of tumors.  None of the ectoposide-treated cell transplants caused tumors whereas 4 of the 5 transplants not treated with ectoposide caused tumors.  This paper appeared in Stem Cells and Development.

The second “good news” paper for iPSCs comes from Junji Takeda at the University of Osaka and Ken Igawa from the Tokyo Medical and Dental University, Japan.   In their paper from Stem Cells Translational Medicine, the Japanese groups collaborated to make iPSCs from skin based fibroblasts and then differentiate them into skin cells (keratinocytes).  However, they made the iPSCs in two different ways.  The first protocol utilized the piggyBac transposon system to make iPSCs.  The piggyBac system comes from moths, but it is highly active in mammalian cells.  It can deliver the genes to the cells, but the segment of DNA is then easily excised from the host cells without causing any mutations.  This system, therefore, will generate iPSCs that do not have any transgenes in them.  The second protocol used a system based on cytomegalovirus that leaves the transgenes in the cells but gradually inactivates their expression.

When these two types of iPSCs were compared, they seems to be essentially identical when grown in culture.  Thus in the pluripotent state, the cells were equivalent for the most part.  But once the iPSC lines were differentiated into skin cells, the transgene-free iPSCs formed skin cells that looked, behaved and had the same gene expression profile as normal human skin cells.  The transgene-containing iPSCs differentiated into skin cells, but they did not look quite like skin cells, did not have the same gene expression profile as normal human skin cells, and did not behave like normal human skin cells.

The moral of this story is that not all iPSC lines are created equally and the way you derive them is as important as the cell type from which they were derived.  Also, even incomplete differentiation does not need to be an obstacle for iPSCs, since the cancer-causing cells can be removed by means of specific drugs.  Finally, not all that glitters is gold.  Cloned embryos may give you stem cells that look more like embryonic stem cells, but so what.  These might still suffer from many of the same set backs.  Add to that the ethical problems with getting women to give up their eggs for research and cures (see Jennifer Lahl’s movie Eggsploitation for more disturbing information about that), and you have a losing combination.

StemCells, Inc., Sued by Former Employee Who Says Their Stem Cell Treatment is Unsafe


A California stem cell company, StemCells, Inc., that is developing cell-based therapies for several different neurological and eye conditions, is being sued by a former employee (whistleblower) who claims that the company did not follow proper protocols in the preparation of their treatments. Rob Williams, who was once a senior manager at StemCells, Inc., has alleged that the company fired him after he brought these problems to the attention of senior management.

According to the Courthouse New Service, Williams in the lawsuit stated that he “noted poor sterile technique, failure to adhere to current Good Manufacturing Practices in the company’s manufacturing process, and substantial deficiencies in the company’s Manual Aseptic Processing of HuCNS-SC (Human Central Nervous System Stem Cells) cell lines—failure and deficiencies that put patients at risk of infection or death during ongoing clinical trials.”

Ken Stratton, who serves as the general counsel for StemCells, Inc., has told the California Stem Cell Report that Williams’s employment “was terminated for performance deficiencies, and [the company] finds no merit to the allegations.” Stratton also said that “the elements of manufacturing practices that concerned Mr. Williams were immediately and carefully reviewed by the company.”

It might be worth noting that this lawsuit coincides with the departure this past April or May of StemCells, Inc.’s Executive VP of Manufacturing Operations and Regulatory Affairs, Stewart Craig, who took a position at Sangamo Biosciences.

Unfortunately for StemCells, Inc., this particular lawsuit comes soon after a second bit of bad press. Embryologist Alan Trounson led the California Institute for Regenerative Medicine (CIRM) until June of this year, but has joined the board of StemCells, Inc., shortly after leaving the state stem cell research funding agency. According to an opinion article written by Ron Leuty, who is a reporter for the San Francisco Business Times, Trounson has recused himself from discussions regarding a loan StemCells, Inc., received from CIRM in 2012 because of his close relationship with the company’s founder. “But the speed of his appointment to the StemCells board has raised questions” about a possible conflict of interest, Leuty wrote.

CIRM has been marred by conflicts of interest accusations since California voters in 2004 birthed CIRM through Proposition 71 and the subsequent sale of $3 billion in state bonds. Now it has one more strike against it.

Leuty called the situation an embarrassment for CIRM. “If the public perceives that individuals—researchers or CIRM employees or company executives—are feeding at the trough of the semiautonomous public agency, it isn’t going to help CIRM get more cash from that very same public that foots the bill.”