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The Effects of Aging on Human Bone Marrow Stromal Cells

The Effects of Aging on Human Bone Marrow Stromal Cells. Alec Richardson 3/17/09. What is Aging?. Changes in an organism over time Can be physiological or behavioral or both Key component is time – Aging seen as the result of numerous changes over time

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The Effects of Aging on Human Bone Marrow Stromal Cells

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  1. The Effects of Aging on Human Bone Marrow Stromal Cells Alec Richardson 3/17/09

  2. What is Aging? • Changes in an organism over time • Can be physiological or behavioral or both • Key component is time – Aging seen as the result of numerous changes over time • Viewed as a decline in function – perhaps better to think of it as a change in function • Affects people differently and the same (m/f) • Different vulnerabilities to disease • Aging results in a higher probability of death • No proven biological basis

  3. Aging Theories • Inside: mechanisms that protect against disease become intrinsically disrupted • Changes in transcription/translation, increased cell death, disruption of organ function • Outside: environment affects genomic integrity or other physiologic parameters • Results in similar changes that lead to vulnerability and malfunction • Probably a mixture of both inside and outside factors • Statistics: Billions of bodily events occur every second • These events can be harmless or harmful based on the genetic makeup of the organism and ‘luck’ • e.g. tumor suppression mechanisms • As the number of events accumulates, the probability of mistakes and problems increases

  4. Aging in Bone • Focus on one particular organ • Intimate relationship between bone and other organs • How does bone change over time in humans? • Disease, disruption in synergy between other organs, changes in cell #, vulnerability to fracture, load bearing capacity • Production of cells, support, storage, detox • Mineralization, stem cells, hormones, immune system, ions, homeostasis

  5. Aging Models • Models of accelerated aging • E.g. w/t mice • Differences between young and old organisms • Artificially aging of organisms

  6. Human Bone Marrow Stromal Cells • Precursor cells in bone are necessary to replenish supplies of vital osteogenic cell types such as osteoblasts • Hypothesis: The aging process results in a decrease in the number of HBMSCs and/or a decrease in the ability of such cells to differentiate and produce mineralization. • If true, this theory could explain why aging results in vulnerability to fracture and diseases such as osteoporosis in older populations

  7. Stem Cell Mesenchymal Stem Cell Osteoprogenitor Pre-osteoblast Osteoblast Possible mechanisms of age-related bone loss BMPs Collagen Osteocalcin Osteopontin Collagenase Other NCPs Mineralization Histone Collagen TGFβ1 Osteopontin Alk Phos BSP Collagen IGF-I, PGE2 Vitamin D Steroids BMPs TGFβ BMPs PTH Runx2 Osx Adipocyte Chondrocytes Myocytes Fibroblasts Osteoblast senescence Bone- Lining cell Osteocyte MSC senescence Lineage switching Transdifferentiation

  8. Experimental Model • CFU-F Assay • Previous papers show CFU-Fs to contain osteoprogenitor cells • Human donors • Young=Age 34-49, Old=Age 70-85 • Stains • Crystal Violet, Alkaline Phosphatase, Alizarin Red • 14 days, 4 re-feedings • Differentiation Factors added to all plates • Β-Glycerophosphate, Ascorbic Acid, Dexamethasone • Seeding density for all plates: 40 cells/cm^2 • Image J software – used for all stains except Aliz. Red

  9. Crystal Violet (+ D.F.) Age 77 Age 43

  10. Alizarin Red Age 77 Age 43

  11. Alkaline Phosphatase Age 77 Age 43

  12. Future Directions • Compare passaged and un-passaged cells • Ficoll gradient to isolate mononuclear cells • Passage to P1 or P2

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