Interesting recent stem cell research

Of the hundreds of publications in the last year relating to stem cells not already reviewed in earlier blog entries, I have selected a few that are particularly interesting for inclusion here.  I start out with three publications that appeared only a few days ago.

Prevention of muscle aging by adult stem cell transplantation

A brand-new publication (November 10 2010) reports an interesting and exciting result Prevention of Muscle Aging by Myofiber-Associated Satellite Cell Transplantation. “We demonstrate that engraftment of myofiber-associated satellite cells, coupled with an induced muscle injury, markedly alters the environment of young adult host muscle, eliciting a near-lifelong enhancement in muscle mass, stem cell number, and force generation. The abrogation of age-related atrophy appears to arise from an increased regenerative capacity of the donor stem cells, which expand to occupy both myonuclei in myofibers and the satellite cell niche. Further, these cells have extensive self-renewal capabilities, as demonstrated by serial transplantation. These near-lifelong, physiological changes suggest an approach for the amelioration of muscle atrophy and diminished function that arise with aging through myofiber-associated satellite cell transplantation.”

Science news reports on the same study in more detail: “The experiments showed that when young host mice with limb muscle injuries were injected with muscle stem cells from young donor mice, the cells not only repaired the injury within days, they caused the treated muscle to double in mass and sustain itself through the lifetime of the transplanted mice. “This was a very exciting and unexpected result,” said Professor Bradley Olwin of CU-Boulder’s molecular, cellular and developmental biology department, the study’s corresponding author. — Muscle stem cells are found within populations of “satellite” cells located between muscle fibers and surrounding connective tissue and are responsible for the repair and maintenance of skeletal muscles, said Olwin. The researchers transplanted between 10 and 50 stem cells along with attached myofibers — which are individual skeletal muscle cells — from the donor mice into the host mice. — “We found that the transplanted stem cells are permanently altered and reduce the aging of the transplanted muscle, maintaining strength and mass,” said Olwin.”

Continuing “ Olwin said the new findings, while intriguing, are only the first in discovering how such research might someday be applicable to human health. —  In healthy skeletal muscle tissue, the population of satellite stem cells is constantly maintained, said Olwin. — “In this study, the hallmarks we see with the aging of muscles just weren’t occurring,” said Olwin. “The transplanted material seemed to kick the stem cells to a high gear for self-renewal, essentially taking over the production of muscle cells. But the team found that when transplanted stem cells and associated myofibers were injected to healthy mouse limb muscles, there was no discernable evidence for muscle mass growth. — “The environment that the stem cells are injected into is very important, because when it tells the cells there is an injury, they respond in a unique way,” he said. “We don’t yet know why the cells we transplanted are not responding to the environment around them in the way that the cells that are already there respond. It’s fascinating, and something we need to understand.” — At the onset of the experiments the research team thought the increase in muscle mass of the transplanted mice with injured legs would dissipate within a few months. Instead, the cells underwent a 50 percent increase in mass and a 170 percent increase in size and remained elevated through the lifetime of the mice — roughly two years, said Olwin.”

I find this result fascinating, a) because the positive changes in muscle mass and strength  induced by the stem transplantation seemed to be permanent and lifelong and, it appeared, free from aging, b) the cell-donor mice had to be young, c) the process would not work unless the recipient mice had muscle injuries.  Because of the similarity of human and mouse muscle biology and stem cell biology, I think the process will quite possibly work the same in humans.  Olwin is quoted as saying “With further research we may one day be able to greatly resist the loss of muscle mass, size and strength in humans that accompanies aging, as well as chronic degenerative diseases like muscular dystrophy.”  I agree with him.

Adult stem cells populations depend on nutrient availability

There is another new (November 2010) study that offers a new perspective on the behavior of adult stem cells in their niches.  The study is based on work with fruit flies.  While the applicability of its results to humans requires further research, it is possible that the pathways involved are evolutionarily conserved.  The relevant publication is Stem Cell Dynamics in Response to Nutrient Availability.  “When nutrient availability becomes limited, animals must actively adjust their metabolism to allocate limited resources and maintain tissue homeostasis [1-3]. However, it is poorly understood how tissues maintained by adult stem cells respond to chronic changes in metabolism. To begin to address this question, we fed flies a diet lacking protein (protein starvation) and assayed both germline and intestinal stem cells. Our results revealed a decrease in stem cell proliferation and a reduction in stem cell number; however, a small pool of active stem cells remained. Upon refeeding, stem cell number increased dramatically, indicating that the remaining stem cells are competent to respond quickly to changes in nutritional status. Stem cell maintenance is critically dependent upon intrinsic and extrinsic factors that act to regulate stem cell behavior [4]. Activation of the insulin/IGF signaling pathway in stem cells and adjacent support cells in the germline was sufficient to suppress stem cell loss during starvation. Therefore, our data indicate that stem cells can directly sense changes in the systemic environment to coordinate their behavior with the nutritional status of the animal, providing a paradigm for maintaining tissue homeostasis under metabolic stress.”

According to a Salk Institute press release as reported in Science News: “When the researchers fed their flies a “poor,” proteinless diet, the levels of circulating insulin-like peptides plummeted, the testes of starved flies became progressively thinner, and stem cell numbers started to decline. Upon re-feeding, insulin-like peptide expression and stem cell numbers recovered quickly. “We found that in starved flies there are fewer stem cells and they divide slower,” says postdoctoral researcher and co-first author Lei Wang, Ph.D. “However, a small pool of active stem cells remained even after prolonged starvation.” — Since germline stem cells are the only cells capable of passing genetic information on to the next generation, the researchers suspected that unique strategies might have been adapted during evolution to protect these stem cells from temporary environmental changes. However, as they discovered, a similar response to protein starvation and re-feeding was demonstrated by another stem cell population—intestinal stem cells present in the midgut. This suggests that the coordination of stem cell maintenance in response to environmental changes represents a conserved strategy utilized across multiple tissues.”

Getting iPSCs to differentiate into desired somatic cell types

The November 2010 publication Differentiation of Functional Cells from iPS Cells by Efficient Gene Transfer discusses how an andovirus vector can be used to transduce transgenes into mouse iPS cells to get those cells to differentiate efficiently into desired somatic cell types, particularly demonstrating differentiation into adipocytes or osteoblasts.   The publication reports “Although establishment of an efficient gene transfer system for iPS cells is considered to be essential for differentiating them into functional cells, the detailed transduction characteristics of iPS cells have not been examined. By using an adenovirus (Ad) vector containing the cytomegalovirus enhancer/beta-actin (CA) promoters, we have developed an efficient transduction system for mouse mesenchymal stem cells and embryonic stem (ES) cells. Also, we applied our transduction system to mouse iPS cells and investigated whether efficient differentiation could be achieved by Ad vector-mediated transduction of a functional gene. As in the case of ES cells, the Ad vector could efficiently transduce transgenes into mouse iPS cells. We found that the CA promoter had potent transduction ability in iPS cells. Moreover, exogenous expression of a PPARγ gene or a Runx2 gene into mouse iPS cells by an optimized Ad vector enhanced adipocyte or osteoblast differentiation, respectively. These results suggest that Ad vector-mediated transient transduction is sufficient to promote cellular differentiation and that our transduction methods would be useful for therapeutic applications based on iPS cells.” 

At the nanoscale level, embryonic stem cells and induced pluripotent stem cells appear to be the same

A May 2010 study Induced pluripotent stem cells at nanoscale reports “Reprogramming of mouse and human somatic cells into induced pluripotent stem (iPS) cells has been made possible with the expression of the transcription factor quartet Oct4, Sox2, c-Myc, and Klf4. Here, we compared iPS cells derived from mouse embryonic fibroblasts with the 4 factors to embryonic stem cells by electron microscopy. Both cell types are almost indistinguishable at the ultrastructural level, providing further evidence for the similarity of these 2 pluripotent stem cell populations.”

iPSCs can themselves reprogram other body cells into iPSC status

Induced pluripotent stem cells (iPSCs) are normally made by exposing normal somatic (body) cells to various combinations of transcription factors in a lengthily laboratory procedure.  But does an iPSC have the power within itself to reprogram normal body cells into iPSC status simply by contact?  The answer appears to be yes.  The February 2010 publication  Reprogramming of somatic cells after fusion with induced pluripotent stem cells and nuclear transfer embryonic stem cells reports “In this study we examine whether a somatic cell, once returned to a pluripotent state, gains the ability to reprogram other somatic cells. We reprogrammed mouse embryonic fibroblasts by viral induction of oct4, sox2, c-myc, and klf-4 genes. Upon fusion of the resulting iPS cells with somatic cells harboring an Oct4-GFP transgene we observed, GFP expression along with activation of Oct4 from the somatic genome, expression of key pluripotency genes, and positive immunostaining for Oct4, SSEA-1, and alkaline phosphatase. The iPS-somatic hybrids had the ability to differentiate into cell types indicative of the three germ layers and were able to localize to the inner cell mass of aggregated embryos. Furthermore, ntES cells were used as fusion partners to generate hybrids, which were also confirmed to be reprogrammed to a pluripotent state. These results demonstrate that once a somatic cell nucleus is reprogrammed, it acquires the capacity and potency to reprogram other somatic cells by cell fusion and shares this functional property with normal embryonic stem (ES) cells.”

Using neural stem/progenitor cells derived from iPSCs to repair spinal cord injuries

The March 2010 oublication Are induced pluripotent stem cells the future of cell-based regenerative therapies for spinal cord injury? Reports “Despite advances in medical and surgical care, current clinical therapies for spinal cord injury (SCI) are limited. During the last two decades, the search for new therapies has been revolutionized by the discovery of stem cells, inspiring scientists and clinicians to search for stem cell-based reparative approaches for many disorders, including neurotrauma. Cell-based therapies using embryonic and adult stem cells in animal models of these disorders have provided positive outcome results. However, the availability of clinically suitable cell sources for human application has been hindered by both technical and ethical issues. The recent discovery of induced pluripotent stem (iPS) cells holds the potential to revolutionize the field of regenerative medicine by offering the option of autologous transplantation, thus eliminating the issue of host rejection. Herein, we will provide the rationale for the use of iPS cells in SCI therapies.”

The June 2010 publication Neural stem cells in regenerative medicine: bridging the gap reports “Repair of the chronically injured spinal presents with multiple challenges, including neuronal/axonal loss and demyelination as a result of primary injury (usually a physical insult), as well as secondary damage, which includes ischemia, inflammation, oxidative injury and glutamatergic toxicity. These processes cause neuronal loss, axonal disruption and lead to a cystic degeneration and an inhibitory astroglial scar. A promising therapeutic intervention for SCI is the use of neural stem cells. Cell replacement strategies using neural precursor cells (NPCs) and oligodendroglial precursor cells (OPCs) have been shown to replace lost/damaged cells, secrete trophic factors, regulate gliosis and scar formation, reduce cystic cavity size and axonal dieback, as well as to enhance plasticity, axonal elongation and neuroprotection. These progenitor cells can be obtained through a variety of sources, including adult neural tissue, embryonic blastocysts and adult somatic cells via induced pluripotent stem cell (iPSC) technology. The use of stem cell technology – especially autologous cell transplantation strategies – in regenerative therapy for SCI holds much promise; these therapies show high potential for clinical translation and for future disease treatment.”

These all appear to be interesting contributions to our knowledge base related to iPSCs and adult stem cells, and strengthen the possibility of realizing the proposed longevity intervention of closing the loop in the stem cell supply chain.