Stem Cells, Health, Technology

The study of dermal adipocytes in the skin is leading to a new understanding of skin phsyiology, how the skin maintains and heals itself, and in the development of new procedures and products for wound healing.  Dr. Valerie Horsley, Ph.D., professor of Molecular, Cellular and Developmental Biology and Dermatology at Yale University has pioneered the work of adipocytes in the skin. Her lab has revealed that adipocytes regenerate in the skin and are essential for regeneration of the hair follicle during its normal growth cycle and following injury (Festa et al., 2011; Schmidt and Horsley, 2013). Working with Dr. Matthew Rodeheffer, Ph.D., professor of comparative medicine at Yale University, has identified mesenchymal adipose progenitor cells in the skin and showed that these cells are necessary to induce hair follicle growth (Festa et al., 2011).  These studies showed that the progenitor cells were activated after injury and required for dermal fibroblast migration during wound healing (Schmidt and Horsley, 2013). Her lab has also shown that dermal adipocyte precursor cell self-renewal process decreases as we age and that this process is dependent on PDGF and IGF-1 signaling from macrophages (Gonzalez et al., 2016).  Further, her lab showed that CD301b marks a portion of midphase macrophages and that depletion of CD301b-expressing macrophages was sufficient to induce skin repair defects observed by depletion of myeloid cells more broadly. Transplanting CD301b⁺ macrophages was sufficient to enhance re-epithelialization, dermal proliferation, and fibroblast repopulation during the midstage wound repair. Additionally, they showed that CD301b-expressing macrophage gene expression was enriched for growth factors and cytokines involved in skin regeneration. Therefore, their results identify a subset of CD301b⁺ macrophages critical for activating skin repair during midstage wound healing.  CD301b⁺ macrophage–derived signaling selectively activated the proliferation of adipocyte progenitor cells and not other myofibroblasts.  PDGFC and IGF1 released from macrophages promoted myofibroblast heterogeneity and repair (Shook et al, 2016; Shook et al, 2018). These data are compatible with the function of macrophages in tissue fibrosis, the ability of exogenous PDGFC to rescue delayed skin wound healing in diabetic mice, and the promotion of fibroblast proliferation and repair by IGF1. Further, the importance of adipose derived mesenchymal stem cells in the skin to polarize macrophages from the M1 inflammatory to a M2 anti-inflammatory phenotype may be important in this adipocyte-mediated process of wound healing (Li et al, 2015).

Another important aspect of adipocytes in the skin is to fight infection. Dr. Richard Gallo, MD, PhD, professor and chief of dermatology at UC San Diego School of Medicine, and colleagues have uncovered a previously unknown role for dermal adipocytes – they produce antimicrobial peptides (AMPs) that help fend off invading bacteria, viruses, and fungi.

So contrary to what many people have been told, Fat Isn’t All Bad, especially when considering adipocytes in the skin.

References

Festa, E et al (2011), Adipocyte lineage cells contribute to the skin stem cell niche to drive hair cycling. Cell 146, 761–71 doi:10.1016/j.cell.2011.07.019pmid:21884937

Gonzalez GC et al (2016) Skin adipocyte stem cell self-renewal is regulated by a PDGFA/AKT-signaling axis. Cell Stem Cell19, 738–751 pmid:27746098

Li Q et al (2015) Skin-Derived Mesenchymal Stem Cells Alleviate Atherosclerosis via Modulating Macrophage Function. Stem Cells Transl Med. 4(11): 1294–1301.

Schmidt V and Horsley V (2013) Intradermal adipocytes mediate fibroblast recruitment during skin wound healing.Development 140, 1517–1527 (2013). doi:10.1242/dev.087593pmid:23482487

Shook,B et al (2016) CD301b+ macrophages are essential for effective skin wound healing. J. Invest. Dermatol. 136, 1885–1891 (2016).doi:10.1016/j.jid.2016.05.107pmid:27287183

Shook B et al (2018) Myofibroblast proliferation and heterogeneity are supported by macrophages during skin repair. Science, DOI: 10.1126/science.aar2971

Careful You May Be Stuck with the Cell’s Phenotype and Genotype for a Very Long Time

Hematopoietic stem and progenitor cells (HSPCs) are responsible for generating and maintaining the extremely diverse pool of blood cells, everything from red blood cells to T-cells, for our lifetime. HSPC transplantation, also known as bone marrow transplantation, remains the only approved stem cell therapy, even though unapproved stem cell transplants for a variety of other indications continue to burgeon. The approved, clinical transplantation of human HSPCs from an allogeneic healthy donor can effectively replenish defective blood cell production caused by congenital or acquired disorders, but, as with most medical products or procedures, there are risks involved. Many case studies have reported the approved stem cell transplants to be associated with the later development of cancer (Cooley et al, 2000), and unapproved stem cell transplant procedures are notorious for side-effects, including development of cancer (Diouhy et al, 2014). Unfortunately, with most drugs and many medical procedures, the long term consequences to health are unknown. Often, when considering drugs, not until Phase IV, postmarket approval are the long term consequence of a drug discovered. Witness the many drugs pulled from market some three to four years after their approval (e.g. ProCon, 2014). Even more unfortunate, the problem is worse with medical procedures (Kumar and Nash, 2011). Such is the case with approved stem cell transplants. The effects of approved stem cell transplants in causing, or being involved, in cancer relapse are not well understood, but are thought to involve epigenetic factors in the stem cells used for the transplant (Christopher et al, 2018). In addition, any type of stem cell transplant may cause aging of the tissue as measured in T-cells using a p16 biomarker (Wood et al, 2016), indicating the increased level of cellular senescence in the surrounding tissue.

So what are some of the possible mechanisms for stem cells to cause these untoward and unpropitious side effects? First, a new study shows that transplanted stem cells (HSPCS) can survive a long time in human patients, such that they can be maintained independently of their continuous production from endogenous HSPCs (Scala et al, 2018). Second, we know that processed stem cells can carry an increasing number of genetic mutations as they are expanded, particularly the p53 mutation associated with many cancer phenotypes (Merkle et al, 2017). And, as I discussed in a previous blog, stem cells have memory, and change their phenotype, for at least many months, when they have experienced a wounding, inflammatory event (Naik et al, 2017). The new phenotype that Naik et al (2017) measured was one of an increased probability to proliferate, a cancer-like cellular behavior. An underlying mechanism for the increased probability of proliferation appeared to be epigenetic, where the DNA was less tightly bound around its histone protein. If we synthesize these data, stem cell transplants using cells that have genotypic, epigenotypic, and phenotypic changes conducive to proliferation, and given the cells ability to engraft, survive, and remain viable for long periods, means that the cells may be a cause of cancer. Coupled with the possible induction of aging in the surrounding tissue (Wood et al, 2016), another risk factor for cancer, stem cell transplants pose a significant risk for cancer, as well as other problems (Maguire, 2016). As such, the problems with stem cell transplants means they should only be used in life threatening conditions, or where their benefits clearly outweigh the risks. The problems with stem cell transplants also leads to the argument for the use of a “systems therapeutic” using stem cell released molecules (Maguire, 2014), instead of the cells (Maguire, 2013), for many indications, such as amytrophic lateral sclerosis and other neurodegenerative diseases (Maguire, 2018).

These issues will be further explored in my second book to be published in 2019.

References

Christopher MJ et al (2018) Immune Escape of Relapsed AML Cells after Allogeneic Transplantation. N. Eng. J. Med, DOI: 10.1056/NEJMoa1808777

Cooley LD et al (2000) Donor cell leukemia: report of a case occurring 11 years after allogeneic bone marrow transplantation and review of the literature. Am.J. Hematol. 63(1):46-53.

Diouhy BJ et al (2014) Autograft-derived spinal cord mass following olfactory mucosal cell transplantation in a spinal cord injury patient. J.  Neurosurgery,  DOI: https://doi.org/10.3171/2014.5.SPINE13992

Kumar S and Nash DB (2011) Health Care Myth Busters: Is There a High Degree of Scientific Certainty in Modern Medicine? Scientific American, March 25, 2011.

Maguire G (2013) Stem cell therapy without the cells. Commun Integr Biol. 6(6):e26631

Maguire G (2014) Systems biology approach to developing “systems therapeutics”. ACS Med. Chem. Lett. 5(5): 453–455

Maguire G (2016) Therapeutics from Adult Stem Cells and the Hype Curve. ACS Med. Che. Lett. 7(5):441-3

Maguire G (2018) Adult Stem Cell Released Molecules: A Paradigm Shift to Systems Therapeutics. Nova Science Publishers, New York.

Merkle FT et al (2017) Human pluripotent stem cells recurrently acquire and expand dominant negative P53 mutations. Nature 545: 229–233

Naik S et al (2017) Inflammatory memory sensitizes skin epithelial stem cells to tissue damage. Nature 550: 475–480

ProCon (2014) 35 FDA-Approved Prescription Drugs Later Pulled from the Market. ProCon, Jan 30, 2014.

Scala S et al (2018) Dynamics of genetically engineered hematopoietic stem and progenitor cells after autologous transplantation in humans. Nature Medicine 24:1683–1690

Wood WA et al (2016) Chemotherapy and Stem Cell Transplantation Increase p16^INK4aExpression, a Biomarker of T-cell Aging. EBioMedicine, 11: 227–238

Why Previously Injured Skin Heals Faster Than Normal

Tissues in our body contain small niches of quiescent adult stem cells that can, upon demand, multiply and differentiate into myriad somatic cell types as required and dictated by environmental demands. In the skin, stem cells can divide and transform into cell types that produce, for example, collagens, pigment, and keratin. Stem cells in the skin also create a secretome that includes signaling molecules and matrix proteins, used for many purposes including to help build the skin’s thick extracellular matrix. Serving as cellular factories for other cell types and a vast array of secreted molecules, the multiple stem cell types in the skin now appear to have another function as recently demonstrated in a collaboration between the laboratories of Dr. Shruti Naik, Ph.D. and Dr. Elaine Fuchs, Ph.D., both of whom are professors at The Rockefeller University (Naik et al, 2017).  Drs. Naik and Fuchs showed that if patches of skin in mice were wounded, causing inflammation, then allowed to heal, subsequent wounds in the same patch of skin would heal about 2.5 times more quickly than adjacent, previously unwounded skin. The effect in previously wounded skin could last up to six months given the conditions of the experiment. This functional adaptation was attributed to epithelial stem cells (EpSCs) and did not require an immune response because skin-resident macrophages and T cells were not involved. What the study showed was that EpSCs maintain chromosomal accessibility, where the DNA is less tightly packed and open to signals from the damaged tissue, at key stress response genes, activated by the inflammatory stimulus. This epigenetic change in the chromatin allowed, during a secondary inflammtory challenge to the same skin patch, genes in that patch of skin to be transcribed rapidly. While the secretome of skin stem cells has previously been shown to be altered by wounding, the exact nature of changes in the secretome was not reported in this study. However, underlying the memory of the stem cells in this study is Aim2, a portion of DNA that encodes an activator of the inflammasome, a conglomerate of proteins that contributes to the skin’s defence against bacteria and viruses. Although having the stem cells remember a wounding event so that future wounds may be more easily healed, like many things in biology where there can be positive effects coupled with potential negative consequences, the epigenetic memory in stem cells may lead to negative cellular behavior, namely overproliferation.  Tumors have often been described as wounds that do not heal.  As Dr. Mina Bissell, Ph.D. at UC Berkeley has taught us, normal tissue homeostasis and architecture inhibit progression of cancer, whereas changes in the microenvironment, such as continuous wounding, can shift the balance of these signals to the procancerous state (Bissell and Hines, 2011). Thus, the constant wounding may change the microenvironment in such a way as to epigenetically shift the stem cells into a very procancerous state, something they remember for a long period of time. An emerging area of research is quickly expanding as scientists continue to explore stem cell memory, and the field of immune-stem cell interactions, and stem cells as a part of the immune system. More about that later.

References

Bissell MJ and Hines WC (2011) Why don’t we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nature Medicine,17:320-329.

Naik S et al (2017) Inflammatory memory sensitizes skin epithelial stem cells to tissue damage. Nature 550:475–480