Sustained Stromal Stem Cell Self-Renewal and Osteoblastic Differentiation During Aging
P.C. Schiller, G. D'Ippolito, G.A. Howard, B.A. Roos
University of Miami Miller School of Medicine and GRECC, Veterans Affairs Medical Center, Miami, FL 33125, USA
We have identified and partially characterized a population of normal
marrow-isolated adult multilineage inducible (MIAMI) cells from males
and females 3- to 72-years-old. These primitive cells are characterized
by the expression of Oct4, Rex1, cMet, Nrtk3, BMPR1B, CD29, CD63, CD81,
CD122, and CD164 among other molecules. Although the frequency of MAIMI
cells, among all marrow nucleated cells, decreases from 0.01% at age 3
to 0.0018% at age 45, their numbers appear to remain unchanged after
this age. The level of expression of the markers characteristic of
MIAMI cells remains constant independent of age and gender. Expression
of genes involved in mitosis, cell cycle regulation, and integrins
associated to muscle development are decreased with aging, while
expression of genes encoding integrins involved in cell migration and
cytokines, and chemokines involved in inflammation are increased with
aging. These data suggest that some cell intrinsic factors may limit
the capacity of MIAMI cells to self-renew, proliferate, or progress
toward specific differentiation programs. In long-term in vitro
expansion experiments with MIAMI cells (above 50 population doublings,
PD), aging increased the PD time by about 20-30%, whereas, specific in
vitro differentiation of MIAMI cells toward osteoblastic cells was
unaffected by age. These results suggest that the intrinsic factors
have a minimal or undetectable effect on the capacity of MIAMI cells to
reach Hayflicks limit or progress toward the osteoblastic
differentiation program, respectively.
We have also examined the effect of cell-to-cell communication on the
osteoblastic differentiation program of murine and human osteoblastic
precursor cells. Stimulation with parathyroid hormone can increase
either proliferation or osteoblastic differentiation depending on the
culture conditions. For stimulation of osteoblastic differentiation,
functional gap-junctional communication mediated by connexin43 is
required. Inhibition of gap-junctional communication not only blocked
the osteoblastic differentiation program but also stimulated the
adipocytic differentiation program. These results suggest that cell
extrinsic factors, such as those that may interfere with hormonal or
gap-junctional communication, could have a greater impact on the
self-renewal or differentiation capacity of marrow progenitor cells
than cell intrinsic factors during aging.
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