Stem Cells as Secret Agents

P E N N Y W O O D

Dr Zoolittle

Stem Cells as Secret Agents

Harnessing the body's foundation of youthful healing

Feed Real Summit, San Diego, October 10-11 2026

Sources:

Listed in the order they appear in the talk.

I work at the applied end, which means almost all of this is other people's research.

The distance between what a laboratory finds and what an animal actually experiences is where I spend my time. If you are working on something that belongs in that gap, or you know of work I should have found and haven't, I would like to hear from you.

Opening: Boris

Point Defiance Zoo & Aquarium. Farewell, Boris. 2020. https://www.pdza.org/farewell-boris/

Question 1: What is a stem cell?

Caplan AI. Mesenchymal stem cells: time to change the name! Stem Cells Transl Med. 2017;6(6):1445-1451. https://doi.org/10.1002/sctm.17-0051

de Witte SFH, Luk F, et al. Immunomodulation by therapeutic mesenchymal stromal cells (MSC) is triggered through phagocytosis of MSC by monocytic cells. Stem Cells. 2018;36(4):602-615. https://doi.org/10.1002/stem.2779

Punzón E, Salgüero R, et al. Equine umbilical cord mesenchymal stem cells demonstrate safety and efficacy in the treatment of canine osteoarthritis: a randomized placebo-controlled trial. J Am Vet Med Assoc. 2022;260(15):1947-1955. https://doi.org/10.2460/javma.22.06.0237

Question 2: Where are they made, and where do they live?

Crisan M, Yap S, et al. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell. 2008;3(3):301-313. https://doi.org/10.1016/j.stem.2008.07.003

Volk SW, Wang Y, et al. Effects of donor characteristics and ex vivo expansion on canine mesenchymal stem cell properties: implications for MSC-based therapies. Cell Transplant. 2012;21(10):2189-2200. https://doi.org/10.3727/096368912X636821

Klymenko SV, Belyi DA, et al. Hematopoietic cell infusion for the treatment of nuclear disaster victims: new data from the Chernobyl accident. Int J Radiat Biol. 2011;87(8):846-850. https://doi.org/10.3109/09553002.2011.560995

Waterman G, Kase K, et al. Selective shielding of bone marrow: an approach to protecting humans from external gamma radiation. Health Phys. 2017;113(3):195-208. https://doi.org/10.1097/HP.0000000000000688

Question 3: How do they work?

Ceradini DJ, Kulkarni AR, et al. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med. 2004;10(8):858-864. https://doi.org/10.1038/nm1075

Madrigal M, Rao KS, et al. A review of therapeutic effects of mesenchymal stem cell secretions and induction of secretory modification by different culture methods. J Transl Med. 2014;12:260. https://doi.org/10.1186/s12967-014-0260-8

Islam MN, Das SR, et al. Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury. Nat Med. 2012;18(5):759-765. https://doi.org/10.1038/nm.2736

Larson BJ, Longaker MT, Lorenz HP. Scarless fetal wound healing: a basic science review. Plast Reconstr Surg. 2010;126(4):1172-1180. https://doi.org/10.1097/PRS.0b013e3181eae781

Werner N, Kosiol S, et al. Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med. 2005;353(10):999-1007. https://doi.org/10.1056/NEJMoa043814

Ross MD, Malone EM, et al. Lower resting and exercise-induced circulating angiogenic progenitors and angiogenic T cells in older men. Am J Physiol Heart Circ Physiol. 2018;314(3):H392-H402. https://doi.org/10.1152/ajpheart.00592.2017

Mandraffino G, Aragona CO, et al. CD34+ cell count predicts long lasting life in the oldest old. Mech Ageing Dev. 2017;164:139-145. https://doi.org/10.1016/j.mad.2017.03.003

Lascelles BDX, Henry JB, et al. Cross-sectional study of the prevalence of radiographic degenerative joint disease in domesticated cats. Vet Surg. 2010;39(5):535-544. https://doi.org/10.1111/j.1532-950X.2010.00708.x

Anderson KL, O'Neill DG, et al. Prevalence, duration and risk factors for appendicular osteoarthritis in a UK dog population under primary veterinary care. Sci Rep. 2018;8:5641. https://doi.org/10.1038/s41598-018-23940-z

Nature's own idea: regeneration across the animal kingdom

Poss KD, Wilson LG, Keating MT. Heart regeneration in zebrafish. Science. 2002;298(5601):2188-2190. https://doi.org/10.1126/science.1077857

Haluza Y, et al. Axolotl epigenetic clocks offer insights into the nature of negligible senescence. bioRxiv preprint. 2024. https://doi.org/10.1101/2024.09.09.611397

McLean KE, Vickaryous MK. A novel amniote model of epimorphic regeneration: the leopard gecko, Eublepharis macularius. BMC Dev Biol. 2011;11:50. https://doi.org/10.1186/1471-213X-11-50

Corwin JT, Cotanche DA. Regeneration of sensory hair cells after acoustic trauma. Science. 1988;240(4860):1772-1774. https://doi.org/10.1126/science.3381100

Seifert AW, Kiama SG, et al. Skin shedding and tissue regeneration in African spiny mice (Acomys). Nature. 2012;489(7417):561-565. https://doi.org/10.1038/nature11499

Qin T, Zhang G, et al. A population of stem cells with strong regenerative potential discovered in deer antlers. Science. 2023;379(6634):840-847. https://doi.org/10.1126/science.add0488

Savina A, Jaffredo T, et al. Single-cell transcriptomics reveals age-resistant maintenance of cell identities, stem cell compartments and differentiation trajectories in long-lived naked mole-rats skin. Aging (Albany NY). 2022;14(9):3728-3756. https://doi.org/10.18632/aging.204054

Question 4: Does my pet still have them?

Caplan AI, Haynesworth SE. Human mesenchymal stem cells. US Patent 5,486,359. 1996. https://patents.google.com/patent/US5486359A/en

Wang T, Ma J, et al. Quantitative translation of dog-to-human aging by conserved remodeling of the DNA methylome. Cell Syst. 2020;11(2):176-185. https://doi.org/10.1016/j.cels.2020.06.006

López-Otín C, Blasco MA, et al. The hallmarks of aging. Cell. 2013;153(6):1194-1217. https://doi.org/10.1016/j.cell.2013.05.039

López-Otín C, Blasco MA, et al. Hallmarks of aging: an expanding universe. Cell. 2023;186(2):243-278. https://doi.org/10.1016/j.cell.2022.11.001

Chang EI, Loh SA, et al. Age decreases endothelial progenitor cell recruitment through decreases in hypoxia-inducible factor 1alpha stabilization during ischemia. Circulation. 2007;116(24):2818-2829. https://doi.org/10.1161/CIRCULATIONAHA.107.715847

Christopherson KW, Hangoc G, et al. Cell surface peptidase CD26/dipeptidylpeptidase IV regulates CXCL12/stromal cell-derived factor-1 alpha-mediated chemotaxis of human cord blood CD34+ progenitor cells. J Immunol. 2002;169(12):7000-7008. https://doi.org/10.4049/jimmunol.169.12.7000

Liu M, Lei H, et al. Adipose-derived mesenchymal stem cells from the elderly exhibit decreased migration and differentiation abilities with senescent properties. Cell Transplant. 2017;26(9):1505-1519. https://doi.org/10.1177/0963689717721221

Question 5: What could they heal? The evidence

Black LL, Gaynor J, et al. Effect of adipose-derived mesenchymal stem and regenerative cells on lameness in dogs with chronic osteoarthritis of the coxofemoral joints: a randomized, double-blinded, multicenter, controlled trial. Vet Ther. 2007;8(4):272-284. https://pubmed.ncbi.nlm.nih.gov/18183546/

Harman R, Carlson K, et al. A prospective, randomized, masked, and placebo-controlled efficacy study of intraarticular allogeneic adipose stem cells for the treatment of osteoarthritis in dogs. Front Vet Sci. 2016;3:81. https://doi.org/10.3389/fvets.2016.00081

Godwin EE, Young NJ, et al. Implantation of bone marrow-derived mesenchymal stem cells demonstrates improved outcome in horses with overstrain injury of the superficial digital flexor tendon. Equine Vet J. 2012;44(1):25-32. https://doi.org/10.1111/j.2042-3306.2011.00363.x

Smith RKW, Werling NJ, et al. Beneficial effects of autologous bone marrow-derived mesenchymal stem cells in naturally occurring tendinopathy. PLoS One. 2013;8(9):e75697. https://doi.org/10.1371/journal.pone.0075697

Canapp SO, Leasure CS, et al. Partial cranial cruciate ligament tears treated with stem cell and platelet-rich plasma combination therapy in 36 dogs: a retrospective study. Front Vet Sci. 2016;3:112. https://doi.org/10.3389/fvets.2016.00112

Canapp SO, Canapp DA, et al. The use of adipose-derived progenitor cells and platelet-rich plasma combination for the treatment of supraspinatus tendinopathy in 55 dogs: a retrospective study. Front Vet Sci. 2016;3:61. https://doi.org/10.3389/fvets.2016.00061

Arzi B, Mills-Ko E, et al. Therapeutic efficacy of fresh, autologous mesenchymal stem cells for severe refractory gingivostomatitis in cats. Stem Cells Transl Med. 2016;5(1):75-86. https://doi.org/10.5966/sctm.2015-0127

Arzi B, Clark KC, et al. Therapeutic efficacy of fresh, allogeneic mesenchymal stem cells for severe refractory feline chronic gingivostomatitis. Stem Cells Transl Med. 2017;6(8):1710-1722. https://doi.org/10.1002/sctm.17-0035

Xuan K, Li B, et al. Deciduous autologous tooth stem cells regenerate dental pulp after implantation into injured teeth. Sci Transl Med. 2018;10(455):eaaf3227. https://doi.org/10.1126/scitranslmed.aaf3227

Pérez-Merino EM, Usón-Casaús JM, et al. Safety and efficacy of allogeneic adipose tissue-derived mesenchymal stem cells for treatment of dogs with inflammatory bowel disease: clinical and laboratory outcomes. Vet J. 2015;206(3):385-390. https://doi.org/10.1016/j.tvjl.2015.08.003

Pérez-Merino EM, et al. Safety and efficacy of allogeneic adipose tissue-derived mesenchymal stem cells for treatment of dogs with inflammatory bowel disease: endoscopic and histological outcomes. Vet J. 2015;206(3):391-397. https://doi.org/10.1016/j.tvjl.2015.07.023

Hall MN, Rosenkrantz WS, et al. Evaluation of the potential use of adipose-derived mesenchymal stromal cells in the treatment of canine atopic dermatitis: a pilot study. Vet Ther. 2010;11(2):E1-14. https://pubmed.ncbi.nlm.nih.gov/20957613/

Kaur G, Ramirez A, et al. A double-blinded placebo-controlled evaluation of adipose-derived mesenchymal stem cells in treatment of canine atopic dermatitis. Vet Res Commun. 2022;46(1):251-260. https://doi.org/10.1007/s11259-021-09853-9

Carlsson PO, Espes D, et al. Umbilical cord-derived mesenchymal stromal cells preserve endogenous insulin production in type 1 diabetes: a Phase I/II randomised double-blind placebo-controlled trial. Diabetologia. 2023;66(8):1431-1441. https://doi.org/10.1007/s00125-023-05934-3

Perin EC, Borow KM, et al. Randomized trial of targeted transendocardial mesenchymal precursor cell therapy in patients with heart failure. J Am Coll Cardiol. 2023;81(9):849-863. https://doi.org/10.1016/j.jacc.2022.11.061

Quimby JM, Webb TL, et al. Safety and efficacy of intravenous infusion of allogeneic cryopreserved mesenchymal stem cells for treatment of chronic kidney disease in cats: results of three sequential pilot studies. Stem Cell Res Ther. 2013;4(2):48. https://doi.org/10.1186/scrt198

Quimby JM, Webb TL, et al. Assessment of intravenous adipose-derived allogeneic mesenchymal stem cells for the treatment of feline chronic kidney disease: a randomized, placebo-controlled clinical trial in eight cats. J Feline Med Surg. 2016;18(2):165-171. https://doi.org/10.1177/1098612X15576980

From the zoo

Point Defiance Zoo & Aquarium. Farewell, Boris. 2020. https://www.pdza.org/farewell-boris/

Colorado State University. First-ever stem cell treatment on a non-human primate a success. 12 August 2020. https://newsmediarelations.colostate.edu/2020/08/12/first-ever-stem-cell-treatment-on-a-non-human-primate-a-success/

University of Sheffield. Stem cells used to successfully treat arthritis in gorilla at Budapest zoo. 29 August 2023. https://sheffield.ac.uk/news/stem-cells-used-successfully-treat-arthritis-gorilla-budapest-zoo

Characterization and administration of allogeneic blood-derived mesenchymal stem cells in an African elephant (Loxodonta africana) with severe osteoarthritis. Zoo veterinary proceedings abstract, Veterinary Information Network. https://vin.com/doc/?id=9948460

Question 6: How can my pet access more?

Question 7: How can I help my pet's own cells every day?

Huffman MA. Animal self-medication and ethno-medicine: exploration and exploitation of the medicinal properties of plants. Proc Nutr Soc. 2003;62(2):371-381. https://doi.org/10.1079/PNS2003257

Jensen GS, Hart AN, et al. Mobilization of human CD34+ CD133+ and CD34+ CD133(-) stem cells in vivo by consumption of an extract from Aphanizomenon flos-aquae: related to modulation of CXCR4 expression by an L-selectin ligand? Cardiovasc Revasc Med. 2007;8(3):189-202. https://doi.org/10.1016/j.carrev.2007.03.004

Drapeau C, Benson KF, et al. Aloe macroclada from Madagascar triggers transient bone marrow stem cell mobilization. J Stem Cell Res Ther. 2015;5(6):1000287. https://doi.org/10.4172/2157-7633.1000287

Drapeau C, Benson KF, et al. Rapid and selective mobilization of specific stem cell types after consumption of a polyphenol-rich extract from sea buckthorn berries (Hippophae) in healthy human subjects. Clin Interv Aging. 2019;14:253-263. https://doi.org/10.2147/CIA.S186893

Irhimeh MR, Fitton JH, et al. Fucoidan ingestion increases the expression of CXCR4 on human CD34+ cells. Exp Hematol. 2007;35(6):989-994. https://doi.org/10.1016/j.exphem.2007.02.009

Frenette PS, Weiss L. Sulfated glycans induce rapid hematopoietic progenitor cell mobilization: evidence for selectin-dependent and independent mechanisms. Blood. 2000;96(7):2460-2468. https://pubmed.ncbi.nlm.nih.gov/11001898/

Hidalgo A, Peired AJ, et al. The integrin alphaMbeta2 anchors hematopoietic progenitors in the bone marrow during enforced mobilization. Blood. 2004;104(4):993-1001. https://doi.org/10.1182/blood-2003-10-3702

Zhu P, Ren Y, et al. Compounds from sea buckthorn and their application in food: a review. Food Chem. 2025;476:143428. https://doi.org/10.1016/j.foodchem.2025.143428

Nazari M, Taheri M, et al. Time-kill curve analysis of fucoidan combination with conventional antibiotics against biofilms formation of methicillin-resistant Staphylococcus aureus and Acinetobacter baumannii clinical isolates. Chemotherapy. 2025;70:53-64. https://doi.org/10.1159/000542826

Gilroy DJ, Kauffman KW, et al. Assessing potential health risks from microcystin toxins in blue-green algae dietary supplements. Environ Health Perspect. 2000;108(5):435-439. https://doi.org/10.1289/ehp.00108435

Marsan DW, Conrad SM, et al. Evaluation of microcystin contamination in blue-green algal dietary supplements using a protein phosphatase inhibition-based test kit. Heliyon. 2018;4(3):e00573. https://doi.org/10.1016/j.heliyon.2018.e00573

The everyday framework

Kröpfl JM, Beltrami FG, et al. Exercise-induced circulating hematopoietic stem and progenitor cells in well-trained subjects. Front Physiol. 2020;11:308. https://doi.org/10.3389/fphys.2020.00308

Tuby H, Maltz L, Oron U. Induction of autologous mesenchymal stem cells in the bone marrow by low-level laser therapy has profound beneficial effects on the infarcted rat heart. Lasers Surg Med. 2011;43(5):401-409. https://doi.org/10.1002/lsm.21063

Cheng CW, Adams GB, et al. Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppression. Cell Stem Cell. 2014;14(6):810-823. https://doi.org/10.1016/j.stem.2014.04.014

Diaz SF, Torres SMF, et al. An analysis of canine hair re-growth after clipping for a surgical procedure. Vet Dermatol. 2004;15(1):25-30. https://doi.org/10.1111/j.1365-3164.2004.00356.x

Research asks about longevity at the level of the molecule. I ask at the level of the lived life.

What wild animals do by default, domestic animals have to be given by design.

Anthropocentric assumption is what we have always imagined. Zoöpocentric evidence is what animals show us. They have been showing us the whole time.

P E N N Y W O O D

Dr Zoolittle