P.C. Schiller, G. D'Ippolito, G.A. Howard, B.A. Roos

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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