A Selection of Recent Regenerative Research

Here I'll point out a varied collection of recent papers and research results linked by the theme of regeneration. I found them interesting enough to note in passing for one reason or another, but a great deal of similar research is passing by these days, far too much for any one individual to read in detail. Regenerative medicine is much more than just the production of effective stem cell treatments. In its broadest definition it also encompasses the sort of rejuvenation therapies outlined in the materials and scientific programs of the SENS Research Foundation. It is a matter of finding the breakage, the abnormality, the injury, and then taking the path of augmenting, altering, or steering cellular activity in order to induce regeneration sufficient to restore normal function. There are countless ways to achieve that goal: tissue engineering for transplantation; cell therapies and small molecule therapies that aim to adjust the behavior of local tissues; augmentations such as gene therapies that introduce entirely new capabilities to cells. Aging is a collection of breakages and damage at the level of cells and proteins that leads to lost functionality. Repairing that damage in order to allow the normal operation of organs and tissues is exactly a facet of regeneration.

Transplantation with induced neural stem cells improves stroke recovery in mice

In a study to determine whether induced neural stem cells (iNSCs), a type of somatic cell directly differentiated into neural stem cells, could exert therapeutic effects when transplanted into mice modeled with ischemic stroke, researchers found that the cells promoted survival and functional recovery. Additionally, they discovered that when administered during the acute phase of stroke, iNSCs protected the brain from ischemia-related damage. In contrast to other studies that have induced somatic cells to become pluripotent stem cells (iPSCs), which can then be differentiated into neural cells, this study directly converted somatic cells into neural stem cells. Researchers concluded that in addition to iNSC transplantation improving survival rate, results also demonstrated reduced infarct volume in the brain and enhanced sensorimotor function in the mice modeled with stroke. "The iNSCs did not produce any adverse responses in the animals, including tumor formation, which may suggest they are safer than regular iPSCs. Further studies are needed to confirm this cell type as a candidate for cell replacement therapy for stroke."

Loss of niche-satellite cell interactions in syndecan-3 null mice alters muscle progenitor cell homeostasis improving muscle regeneration

The skeletal muscle stem cell niche provides an environment that maintains quiescent satellite cells, required for skeletal muscle homeostasis and regeneration. Syndecan-3, a transmembrane proteoglycan expressed in satellite cells, supports communication with the niche, providing cell interactions and signals to maintain quiescent satellite cells. Syndecan-3 ablation unexpectedly improves regeneration in repeatedly injured muscle and in dystrophic mice, accompanied by the persistence of sublaminar and interstitial, proliferating myoblasts. Additionally, muscle aging is improved in syndecan-3 null mice. Since syndecan-3 null myofiber-associated satellite cells downregulate Pax7 and migrate away from the niche more readily than wild type cells, syxndecan-3 appears to regulate satellite cell homeostasis and satellite cell homing to the niche. Manipulating syndecan-3 provides a promising target for development of therapies to enhance muscle regeneration in muscular dystrophies and in aged muscle.

Bursting the unfolded protein response accelerates axonal regeneration

The endoplasmic reticulum (ER) is a dynamic interconnected network involved in quality control processes that maintain a functional proteome in the cell. Accumulating evidence indicates that central nervous system and peripheral nervous system injury alters ER proteostasis engaging a stress reaction in neurons and glial cells. ER stress activates an adaptive mechanism to cope with protein folding alterations, known as the unfolded protein response (UPR). We recently investigated the impact of the UPR to peripheral nerve regeneration. Using genetic manipulation, we studied the consequences of targeting XBP1 to assess the impact of the UPR to Wallerian degeneration after sciatic nerve damage. Deletion of Xbp1 in the nervous system led to decreased myelin clearance, axonal regeneration and macrophage infiltration after mechanical damage. Importantly, locomotor recovery in Xbp1 deficient mice was significantly delayed. Furthermore, overexpression of XBP1s in neurons using a transgenic mice increased axonal regeneration and locomotor recovery after injury. We moved forward and developed a therapeutic strategy to artificially engage XBP1-dependent gene expression programs to enhance axonal repair. We validated a gene transfer approach to deliver XBP1s into sensory axons using adeno-associated viruses (AAVs). AAV-XBP1s transduced neurons showed an enhancement in the axonal regeneration process. Altogether, these results demonstrated a differential contribution of the IRE1α/XBP1 signaling branch of the UPR in the injured peripheral nervous system.

We speculate that the local activation of UPR stress sensors in the axonal compartment after damage may trigger the retrograde transport of active XBP1s to engage transcriptional programs that contribute to alleviate proteostasis alterations. The next step in the field is to determine if the UPR has therapeutic potential. Overall, modulation of axonal regeneration programs by the UPR incorporates novel players in the process of nerve repair after mechanical damage. Since several small molecules and gene therapy strategies are available to target the UPR, manipulation of the ER proteostasis network might emerge as a new avenue to develop interventions that improve axonal regeneration in different degenerative conditions of the nervous system.

Rejuvenating Muscle Stem Cell Function: Restoring Quiescence and Overcoming Senescence

Elderly humans gradually lose strength and the capacity to repair skeletal muscle. Skeletal muscle repair requires functional skeletal muscle satellite (or stem) cells (SMSCs) and progenitor cells. Diminished stem cell numbers and increased dysfunction correlate with the observed gradual loss of strength during aging. Recent reports attribute the loss of stem cell numbers and function to either increased entry into a presenescent state or the loss of self-renewal capacity due to an inability to maintain quiescence resulting in stem cell exhaustion. Earlier work has shown that exposure to factors from blood of young animals and other treatments could restore SMSC function. However, cells in the presenescent state are refractory to the beneficial effects of being transplanted into a young environment. Entry into the presenescent state results from loss of autophagy, leading to increased reactive oxygen species and epigenetic modification at the CDKN2A locus, upregulating cell senescence biomarker p16ink4a. However, the presenescent SMSCs can be rejuvenated by agents that stimulate autophagy, such as the mTOR inhibitor rapamycin. Autophagy plays a critical role in SMSC homeostasis. These results have implications for the development of senolytic therapies that attempt to destroy p16ink4a expressing cells, since such therapies would also destroy a reservoir of potentially rescuable regenerative stem cells. Other work suggests that in humans, loss of SMSC self-renewal capacity is primarily due to decreased expression of sprouty1. DNA hypomethylation at the SPRY1 gene locus downregulates sprouty1, causing inability to maintain quiescence and eventual exhaustion of the stem cell population. A unifying hypothesis posits that in aging humans, first loss of quiescence occurs, depleting the stem cell population, but that remaining SMSCs are increasingly subject to presenescence in the very old.

Researchers amplify regeneration of spinal nerve cells

Researchers successfully boosted the regeneration of mature nerve cells in the spinal cords of adult mammals - an achievement that could one day translate into improved therapies for patients with spinal cord injuries. "This research lays the groundwork for regenerative medicine for spinal cord injuries. We have uncovered critical molecular and cellular checkpoints in a pathway involved in the regeneration process that may be manipulated to boost nerve cell regeneration after a spinal injury." The researchers focused on glial cells, the most abundant non-neuronal type of cells in the central nervous system. Glial cells support nerve cells in the spinal cord and form scar tissue in response to injury. In 2013 and 2014, researchers created new nerve cells in the brains and spinal cords of mice by introducing transcription factors that promoted the transition of adult glial cells into more primitive, stem cell-like states, and then coaxed them to mature into adult nerve cells. The number of new spinal nerve cells generated by this process was low, however, leading researchers to focus on ways to amplify adult neuron production.

In a two-step process, researchers first silenced parts of the p53-p21 protein pathway that acts as a roadblock to the reprogramming of glial cells into the more primitive, stem-like types of cells with potential to become nerve cells. Although the blockade was successfully lifted, many cells failed to advance past the stem cell-like stage. In the second step, mice were screened for factors that could boost the number of stem-like cells that matured into adult neurons. They identified two growth factors - BDNF and Noggin - that accomplished this goal. Using this approach, researchers increased the number of newly matured neurons by tenfold. "Our ability to successfully produce a large population of long-lived and diverse subtypes of new neurons in the adult spinal cord provides a cellular basis for regeneration-based therapy for spinal cord injuries. If borne out by future studies, this strategy would pave the way for using a patient's own glial cells, thereby avoiding transplants and the need for immunosuppressive therapy."

Reconstituted high-density lipoproteins promote wound repair and blood flow recovery in response to ischemia in aged mice

The average population age is increasing and the incidence of age-related vascular complications is rising in parallel. Impaired wound healing and disordered ischemia-mediated angiogenesis are key contributors to age-impaired vascular complications that can lead to amputation. High-density lipoproteins (HDL) have vasculo-protective properties and augment ischemia-driven angiogenesis in young animals. We aimed to determine the effect of reconstituted HDL (rHDL) on aged mice in a murine wound healing model and the hindlimb ischemia (HLI) model.

Daily topical application of rHDL increased the rate of wound closure by Day 7 post-wounding (25%). Wound blood perfusion, a marker of angiogenesis, was elevated in rHDL treated wounds (Days 4-10 by 22-25%). In addition, rHDL increased wound capillary density by 52.6%. In the HLI model, rHDL infusions augmented blood flow recovery in ischemic limbs (Day 18 by 50% and Day 21 by 88%) and prevented tissue necrosis and toe loss. Assessment of capillary density in ischemic hindlimb sections found a 90% increase in rHDL infused animals. In vitro studies in fibroblasts isolated from aged mice found that incubation with rHDL was able to significantly increase the key pro-angiogenic mediator vascular endothelial growth factor (VEGF) protein (25%). In conclusion, rHDL can promote wound healing and wound angiogenesis, and blood flow recovery in response to ischemia in aged mice. Mechanistically, this is likely to be via an increase in VEGF. This highlights a potential role for HDL in the therapeutic modulation of age-impaired vascular complications.

Comments

I am so glad stem cells research in going strong, it will play big role in rejuvenation.

In my opinion tissue engineering will be very important for first crude rejuvenation therapies, after we master stem cells we will mostly do cell therapies, tissue engineering will only be used for organs which are beyond repair.

Posted by: RS at November 19th, 2016 4:18 PM

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